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Cochrane Review bolsters case that emollients don’t prevent AD
associated with early use of emollients.
The document, published in November 2022, updates a February 2021 version, said Robert Boyle, MD, PhD, senior author of the Cochrane Review and a pediatric allergist at Imperial College London. “The differences were slight,” he told this news organization. “Mainly, we had a little more data about food allergy outcomes, which slightly strengthened the concern about a possible increase in food allergy with emollients; and we had some new genetic information, which allowed us to add some further interaction analyses and confirm that chromosome 11 intergenic variant rs2212434 doesn’t seem to impact the effect – or lack of effect – of emollient on eczema development.”
The updated Cochrane Review concludes that, “based on low‐ to moderate-certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection.”
The latest publication should strengthen clinicians’ confidence in not recommending emollient use for preventing AD in at-risk infants – however, that message is being diluted by a stream of contradictory conclusions from poor-quality systematic reviews, say Dr. Boyle and two coauthors. “It’s a systematic problem of people churning out endless systematic reviews without much rigor,” explained the lead author Maeve Kelleher, MD, from Children’s Health Ireland, Crumlin. There have been “misleading systematic reviews published, often in high-ranking journals,” agreed Dr. Boyle.
“I have been an advocate of systematic reviews for the last 20 years, but they have gone completely out of control,” added Hywel Williams, MD, PhD, another of the Cochrane Review coauthors, who is professor of dermato-epidemiology and codirector of the Centre of Evidence Based Dermatology, at Nottingham (England) University Hospitals NHS Trust. In an editorial, published last year, Dr. Williams even posed the question: “Are Dermatology Systematic Reviews Spinning Out of Control?” in which he blamed “the misrepresentation of study results” – which he calls “the sin of spin” – for degrading the quality of science in dermatology.
“The field has become a ‘sausage machine’ industry that undermines the value of systematic reviews in providing a summary of the best evidence to inform patient care,” he wrote. “Fewer systematic reviews are needed in dermatology,” but “better ones” are needed, he continued, calling for all systematic reviews to be registered prospectively, and reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
Earlier this year, in a letter to the editor, Dr. Kelleher, Dr. Boyle, Dr. Williams, and several others outlined their concerns after a systemic review and meta-analysis was published, “which came to very different conclusions” than their Cochrane Review.
“It is quite common to see non-Cochrane reviews published in leading specialty journals, which interpret data in a more positive light than Cochrane reviews, which have assessed a similar dataset/topic,” Dr. Boyle said in the interview.
Such concerns also apply to the publication of another systematic review that was recently published. “Overall, early application of emollients is an effective strategy for preventing AD development in high-risk infants,” reported senior author Xiaojing Kang, MD, PhD, from People’s Hospital of Xinjiang Uygur Autonomous Region, Urumchi, China, and coauthors, who could not be reached for comment. In their discussion, the authors cite several criticisms of the Cochrane Review: that it included two meeting abstracts and two “ineligible” studies; did not do subgroup analysis of high-risk infants; did not look at different types of emollients; and did not examine the risk of food sensitization.
“A Cochrane Review can be quite a large and complex document to negotiate for those who are not very familiar with Cochrane’s methodology,” said Dr. Boyle. He dismissed the criticism, saying “we did do subgroup analysis of high risk infants, we did look at different types of emollient, and we did look at food sensitization and food allergy risk. We only included eligible studies. … Certainly we would include abstracts of trials, which are not reported in any other form, in order to capture as complete a picture.”
Ultimately, Dr. Boyle said, the discrepancy in conclusions between such systematic reviews and the Cochrane Review relates to quality of methodology. “Our Cochrane review was an individual participant data (IPD) meta-analysis, meaning that authors of the main trials in this area shared their original datasets with us,” he said in the interview. “This is the ‘gold standard’ in systematic reviews, and allowed us to check data/ query inconsistencies and to apply a single-analysis methodology across all studies. It also allowed us to undertake some analyses, which are just not possible in aggregate data analysis based on published work without IPD.”
The most recently published systematic review had no registered protocol, “so, there is no transparency about the methods used,” he noted. “It is free and simple to register a protocol – multiple websites such as PROSPERO, open science framework, and zenodo allow this,” he said “In the journal I edit, we use availability of a registered protocol as a marker of quality. We find that systematic reviews with no registered protocol are almost universally poor quality.”
Dr. Williams is a founding member and coordinating editor of the Cochrane Skin Group 1998 to 2017. Dr. Boyle was paid by Cochrane for senior editor work, until recently, and had no other relevant disclosures. Dr. Kelleher had no relevant disclosures.
associated with early use of emollients.
The document, published in November 2022, updates a February 2021 version, said Robert Boyle, MD, PhD, senior author of the Cochrane Review and a pediatric allergist at Imperial College London. “The differences were slight,” he told this news organization. “Mainly, we had a little more data about food allergy outcomes, which slightly strengthened the concern about a possible increase in food allergy with emollients; and we had some new genetic information, which allowed us to add some further interaction analyses and confirm that chromosome 11 intergenic variant rs2212434 doesn’t seem to impact the effect – or lack of effect – of emollient on eczema development.”
The updated Cochrane Review concludes that, “based on low‐ to moderate-certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection.”
The latest publication should strengthen clinicians’ confidence in not recommending emollient use for preventing AD in at-risk infants – however, that message is being diluted by a stream of contradictory conclusions from poor-quality systematic reviews, say Dr. Boyle and two coauthors. “It’s a systematic problem of people churning out endless systematic reviews without much rigor,” explained the lead author Maeve Kelleher, MD, from Children’s Health Ireland, Crumlin. There have been “misleading systematic reviews published, often in high-ranking journals,” agreed Dr. Boyle.
“I have been an advocate of systematic reviews for the last 20 years, but they have gone completely out of control,” added Hywel Williams, MD, PhD, another of the Cochrane Review coauthors, who is professor of dermato-epidemiology and codirector of the Centre of Evidence Based Dermatology, at Nottingham (England) University Hospitals NHS Trust. In an editorial, published last year, Dr. Williams even posed the question: “Are Dermatology Systematic Reviews Spinning Out of Control?” in which he blamed “the misrepresentation of study results” – which he calls “the sin of spin” – for degrading the quality of science in dermatology.
“The field has become a ‘sausage machine’ industry that undermines the value of systematic reviews in providing a summary of the best evidence to inform patient care,” he wrote. “Fewer systematic reviews are needed in dermatology,” but “better ones” are needed, he continued, calling for all systematic reviews to be registered prospectively, and reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
Earlier this year, in a letter to the editor, Dr. Kelleher, Dr. Boyle, Dr. Williams, and several others outlined their concerns after a systemic review and meta-analysis was published, “which came to very different conclusions” than their Cochrane Review.
“It is quite common to see non-Cochrane reviews published in leading specialty journals, which interpret data in a more positive light than Cochrane reviews, which have assessed a similar dataset/topic,” Dr. Boyle said in the interview.
Such concerns also apply to the publication of another systematic review that was recently published. “Overall, early application of emollients is an effective strategy for preventing AD development in high-risk infants,” reported senior author Xiaojing Kang, MD, PhD, from People’s Hospital of Xinjiang Uygur Autonomous Region, Urumchi, China, and coauthors, who could not be reached for comment. In their discussion, the authors cite several criticisms of the Cochrane Review: that it included two meeting abstracts and two “ineligible” studies; did not do subgroup analysis of high-risk infants; did not look at different types of emollients; and did not examine the risk of food sensitization.
“A Cochrane Review can be quite a large and complex document to negotiate for those who are not very familiar with Cochrane’s methodology,” said Dr. Boyle. He dismissed the criticism, saying “we did do subgroup analysis of high risk infants, we did look at different types of emollient, and we did look at food sensitization and food allergy risk. We only included eligible studies. … Certainly we would include abstracts of trials, which are not reported in any other form, in order to capture as complete a picture.”
Ultimately, Dr. Boyle said, the discrepancy in conclusions between such systematic reviews and the Cochrane Review relates to quality of methodology. “Our Cochrane review was an individual participant data (IPD) meta-analysis, meaning that authors of the main trials in this area shared their original datasets with us,” he said in the interview. “This is the ‘gold standard’ in systematic reviews, and allowed us to check data/ query inconsistencies and to apply a single-analysis methodology across all studies. It also allowed us to undertake some analyses, which are just not possible in aggregate data analysis based on published work without IPD.”
The most recently published systematic review had no registered protocol, “so, there is no transparency about the methods used,” he noted. “It is free and simple to register a protocol – multiple websites such as PROSPERO, open science framework, and zenodo allow this,” he said “In the journal I edit, we use availability of a registered protocol as a marker of quality. We find that systematic reviews with no registered protocol are almost universally poor quality.”
Dr. Williams is a founding member and coordinating editor of the Cochrane Skin Group 1998 to 2017. Dr. Boyle was paid by Cochrane for senior editor work, until recently, and had no other relevant disclosures. Dr. Kelleher had no relevant disclosures.
associated with early use of emollients.
The document, published in November 2022, updates a February 2021 version, said Robert Boyle, MD, PhD, senior author of the Cochrane Review and a pediatric allergist at Imperial College London. “The differences were slight,” he told this news organization. “Mainly, we had a little more data about food allergy outcomes, which slightly strengthened the concern about a possible increase in food allergy with emollients; and we had some new genetic information, which allowed us to add some further interaction analyses and confirm that chromosome 11 intergenic variant rs2212434 doesn’t seem to impact the effect – or lack of effect – of emollient on eczema development.”
The updated Cochrane Review concludes that, “based on low‐ to moderate-certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection.”
The latest publication should strengthen clinicians’ confidence in not recommending emollient use for preventing AD in at-risk infants – however, that message is being diluted by a stream of contradictory conclusions from poor-quality systematic reviews, say Dr. Boyle and two coauthors. “It’s a systematic problem of people churning out endless systematic reviews without much rigor,” explained the lead author Maeve Kelleher, MD, from Children’s Health Ireland, Crumlin. There have been “misleading systematic reviews published, often in high-ranking journals,” agreed Dr. Boyle.
“I have been an advocate of systematic reviews for the last 20 years, but they have gone completely out of control,” added Hywel Williams, MD, PhD, another of the Cochrane Review coauthors, who is professor of dermato-epidemiology and codirector of the Centre of Evidence Based Dermatology, at Nottingham (England) University Hospitals NHS Trust. In an editorial, published last year, Dr. Williams even posed the question: “Are Dermatology Systematic Reviews Spinning Out of Control?” in which he blamed “the misrepresentation of study results” – which he calls “the sin of spin” – for degrading the quality of science in dermatology.
“The field has become a ‘sausage machine’ industry that undermines the value of systematic reviews in providing a summary of the best evidence to inform patient care,” he wrote. “Fewer systematic reviews are needed in dermatology,” but “better ones” are needed, he continued, calling for all systematic reviews to be registered prospectively, and reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
Earlier this year, in a letter to the editor, Dr. Kelleher, Dr. Boyle, Dr. Williams, and several others outlined their concerns after a systemic review and meta-analysis was published, “which came to very different conclusions” than their Cochrane Review.
“It is quite common to see non-Cochrane reviews published in leading specialty journals, which interpret data in a more positive light than Cochrane reviews, which have assessed a similar dataset/topic,” Dr. Boyle said in the interview.
Such concerns also apply to the publication of another systematic review that was recently published. “Overall, early application of emollients is an effective strategy for preventing AD development in high-risk infants,” reported senior author Xiaojing Kang, MD, PhD, from People’s Hospital of Xinjiang Uygur Autonomous Region, Urumchi, China, and coauthors, who could not be reached for comment. In their discussion, the authors cite several criticisms of the Cochrane Review: that it included two meeting abstracts and two “ineligible” studies; did not do subgroup analysis of high-risk infants; did not look at different types of emollients; and did not examine the risk of food sensitization.
“A Cochrane Review can be quite a large and complex document to negotiate for those who are not very familiar with Cochrane’s methodology,” said Dr. Boyle. He dismissed the criticism, saying “we did do subgroup analysis of high risk infants, we did look at different types of emollient, and we did look at food sensitization and food allergy risk. We only included eligible studies. … Certainly we would include abstracts of trials, which are not reported in any other form, in order to capture as complete a picture.”
Ultimately, Dr. Boyle said, the discrepancy in conclusions between such systematic reviews and the Cochrane Review relates to quality of methodology. “Our Cochrane review was an individual participant data (IPD) meta-analysis, meaning that authors of the main trials in this area shared their original datasets with us,” he said in the interview. “This is the ‘gold standard’ in systematic reviews, and allowed us to check data/ query inconsistencies and to apply a single-analysis methodology across all studies. It also allowed us to undertake some analyses, which are just not possible in aggregate data analysis based on published work without IPD.”
The most recently published systematic review had no registered protocol, “so, there is no transparency about the methods used,” he noted. “It is free and simple to register a protocol – multiple websites such as PROSPERO, open science framework, and zenodo allow this,” he said “In the journal I edit, we use availability of a registered protocol as a marker of quality. We find that systematic reviews with no registered protocol are almost universally poor quality.”
Dr. Williams is a founding member and coordinating editor of the Cochrane Skin Group 1998 to 2017. Dr. Boyle was paid by Cochrane for senior editor work, until recently, and had no other relevant disclosures. Dr. Kelleher had no relevant disclosures.
FROM THE COCHRANE REVIEW
A single pediatric CT scan raises brain cancer risk
Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.
“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.
“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.
“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.
The study was published online in The Lancet Oncology.
“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.
“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”
“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”
Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”
She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
Dose/response relationship
The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.
The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.
During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.
The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.
“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.
These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.
“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
Keeping dose to a minimum
The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.
“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.
“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”
The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.
“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.
“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.
“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.
The study was published online in The Lancet Oncology.
“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.
“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”
“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”
Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”
She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
Dose/response relationship
The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.
The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.
During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.
The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.
“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.
These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.
“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
Keeping dose to a minimum
The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.
“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.
“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”
The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.
“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.
“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.
“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.
The study was published online in The Lancet Oncology.
“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.
“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”
“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”
Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”
She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
Dose/response relationship
The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.
The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.
During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.
The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.
“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.
These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.
“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
Keeping dose to a minimum
The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.
“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.
“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”
The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET ONCOLOGY
Study comparing surgical and N95 masks sparks concern
The study’s senior author is John Conly, MD, an infectious disease specialist and professor at the University of Calgary (Alta.), and Alberta Health Services. The findings are not consistent with those of many other studies on this topic.
Commenting about Dr. Conly’s study, Eric Topol, MD, editor-in-chief of Medscape, wrote: “It’s woefully underpowered but ruled out a doubling of hazard for use of medical masks.”
The study, which was partially funded by the World Health Organization, was published online in Annals of Internal Medicine.
This is not the first time that Dr. Conly, who also advises the WHO, has been the subject of controversy. He previously denied that COVID-19 is airborne – a position that is contradicted by strong evidence. In 2021, Dr. Conly made headlines with his controversial claim that N95 respirators can cause harms, including oxygen depletion and carbon dioxide retention.
A detailed examination by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis, pointed out numerous scientific flaws in the study, including inconsistent use of both types of masks. The study also examined health care workers in four very different countries (Canada, Israel, Egypt, and Pakistan) during different periods of the pandemic, which may have affected the results. Furthermore, the study did not account for vaccination status and lacked a control group. CIDRAP receives funding from 3M, which makes N95 respirators.
In a commentary published alongside the study, Roger Chou, MD, professor of medicine at Oregon Health & Science University, Portland, said that the results were “not definitive,” with “a generous noninferiority threshold” that is actually “consistent with up to a relative 70% increased risk ... which may be unacceptable to many health workers.”
Lead study author Mark Loeb, MD, professor of infectious diseases at McMaster University, Hamilton, Ont., defended the findings. “The confidence intervals around this, that is, what the possible results could be if the trial was repeated many times, range from −2.5% to 4.9%,” he told this news organization. “This means that the risk of a COVID-19 infection in those using the medical masks could have ranged from anywhere from 2.5% reduction in risk to a 4.9% increase in risk. Readers and policy makers can decide for themselves about this.”
“There is no point continuing to run underpowered, poorly designed studies that are designed to confirm existing biases,” Raina MacIntyre, PhD, professor of global biosecurity and head of the Biosecurity Program at the Kirby Institute, Sydney, said in an interview. “The new study in Annals of Internal Medicine is entirely consistent with our finding that to prevent infection, you need an N95, and it needs to be worn throughout the whole shift. A surgical mask and intermittent use of N95 are equally ineffective. This should not surprise anyone, given a surgical mask is not designed as respiratory protection but is designed to prevent splash or spray of liquid on the face. Only a respirator is designed as respiratory protection through both the seal around the face and the filter of the face piece to prevent inhalation of virus laden aerosols, but you need to wear it continually in a high-risk environment like a hospital.”
“It makes zero sense to do a randomized trial on something you can measure directly,” said Kimberly Prather, PhD, an atmospheric chemist, professor, and director of the NSF Center for Aerosol Impacts on Chemistry of the Environment at the University of California, San Diego. “In fact, many studies have shown aerosols leaking out of surgical masks. Surgical masks are designed to block large spray droplets. Aerosols (0.5-3 mcm), which have been shown to contain infectious SARS-CoV-2 virus, travel with the air flow, and escape.”
“This study ... will be used to justify policies of supplying health care workers, and perhaps patients and visitors, too, with inadequate protection,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford (England), told this news organization.
“These authors have been pushing back against treating COVID as airborne for 3 years,” David Fisman, MD, an epidemiologist and infectious disease specialist at the University of Toronto, said in an interview. “So, you’ll see these folks brandishing this very flawed trial to justify continuing the infection control practices that have been so disastrous throughout the pandemic.”
The study was funded by the World Health Organization, the Canadian Institutes of Health Research, and the Juravinski Research Institute. Dr. Conly reported receiving grants from the Canadian Institutes for Health Research, Pfizer, and the WHO. Dr. Chou disclosed being a methodologist for WHO guidelines on infection prevention and control measures for COVID-19. Dr. Loeb disclosed payment for expert testimony on personal protective equipment from the government of Manitoba and the Peel District School Board. Dr. MacIntyre has led a large body of research on masks and respirators in health workers, including four randomized clinical trials. She is the author of a book, “Dark Winter: An insider’s guide to pandemics and biosecurity” (Syndey: NewSouth Publishing, 2022), which covers the history and politics of the controversies around N95 and masks. Dr. Prather reported no disclosures. Dr. Greenhalgh is a member of Independent SAGE and an unpaid adviser to the philanthropic fund Balvi. Dr. Fisman has served as a paid legal expert for the Ontario Nurses’ Association in their challenge to Directive 5, which restricted access to N95 masks in health care. He also served as a paid legal expert for the Elementary Teachers’ Federation of Ontario in its efforts to make schools safer in Ontario.
A version of this article first appeared on Medscape.com.
The study’s senior author is John Conly, MD, an infectious disease specialist and professor at the University of Calgary (Alta.), and Alberta Health Services. The findings are not consistent with those of many other studies on this topic.
Commenting about Dr. Conly’s study, Eric Topol, MD, editor-in-chief of Medscape, wrote: “It’s woefully underpowered but ruled out a doubling of hazard for use of medical masks.”
The study, which was partially funded by the World Health Organization, was published online in Annals of Internal Medicine.
This is not the first time that Dr. Conly, who also advises the WHO, has been the subject of controversy. He previously denied that COVID-19 is airborne – a position that is contradicted by strong evidence. In 2021, Dr. Conly made headlines with his controversial claim that N95 respirators can cause harms, including oxygen depletion and carbon dioxide retention.
A detailed examination by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis, pointed out numerous scientific flaws in the study, including inconsistent use of both types of masks. The study also examined health care workers in four very different countries (Canada, Israel, Egypt, and Pakistan) during different periods of the pandemic, which may have affected the results. Furthermore, the study did not account for vaccination status and lacked a control group. CIDRAP receives funding from 3M, which makes N95 respirators.
In a commentary published alongside the study, Roger Chou, MD, professor of medicine at Oregon Health & Science University, Portland, said that the results were “not definitive,” with “a generous noninferiority threshold” that is actually “consistent with up to a relative 70% increased risk ... which may be unacceptable to many health workers.”
Lead study author Mark Loeb, MD, professor of infectious diseases at McMaster University, Hamilton, Ont., defended the findings. “The confidence intervals around this, that is, what the possible results could be if the trial was repeated many times, range from −2.5% to 4.9%,” he told this news organization. “This means that the risk of a COVID-19 infection in those using the medical masks could have ranged from anywhere from 2.5% reduction in risk to a 4.9% increase in risk. Readers and policy makers can decide for themselves about this.”
“There is no point continuing to run underpowered, poorly designed studies that are designed to confirm existing biases,” Raina MacIntyre, PhD, professor of global biosecurity and head of the Biosecurity Program at the Kirby Institute, Sydney, said in an interview. “The new study in Annals of Internal Medicine is entirely consistent with our finding that to prevent infection, you need an N95, and it needs to be worn throughout the whole shift. A surgical mask and intermittent use of N95 are equally ineffective. This should not surprise anyone, given a surgical mask is not designed as respiratory protection but is designed to prevent splash or spray of liquid on the face. Only a respirator is designed as respiratory protection through both the seal around the face and the filter of the face piece to prevent inhalation of virus laden aerosols, but you need to wear it continually in a high-risk environment like a hospital.”
“It makes zero sense to do a randomized trial on something you can measure directly,” said Kimberly Prather, PhD, an atmospheric chemist, professor, and director of the NSF Center for Aerosol Impacts on Chemistry of the Environment at the University of California, San Diego. “In fact, many studies have shown aerosols leaking out of surgical masks. Surgical masks are designed to block large spray droplets. Aerosols (0.5-3 mcm), which have been shown to contain infectious SARS-CoV-2 virus, travel with the air flow, and escape.”
“This study ... will be used to justify policies of supplying health care workers, and perhaps patients and visitors, too, with inadequate protection,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford (England), told this news organization.
“These authors have been pushing back against treating COVID as airborne for 3 years,” David Fisman, MD, an epidemiologist and infectious disease specialist at the University of Toronto, said in an interview. “So, you’ll see these folks brandishing this very flawed trial to justify continuing the infection control practices that have been so disastrous throughout the pandemic.”
The study was funded by the World Health Organization, the Canadian Institutes of Health Research, and the Juravinski Research Institute. Dr. Conly reported receiving grants from the Canadian Institutes for Health Research, Pfizer, and the WHO. Dr. Chou disclosed being a methodologist for WHO guidelines on infection prevention and control measures for COVID-19. Dr. Loeb disclosed payment for expert testimony on personal protective equipment from the government of Manitoba and the Peel District School Board. Dr. MacIntyre has led a large body of research on masks and respirators in health workers, including four randomized clinical trials. She is the author of a book, “Dark Winter: An insider’s guide to pandemics and biosecurity” (Syndey: NewSouth Publishing, 2022), which covers the history and politics of the controversies around N95 and masks. Dr. Prather reported no disclosures. Dr. Greenhalgh is a member of Independent SAGE and an unpaid adviser to the philanthropic fund Balvi. Dr. Fisman has served as a paid legal expert for the Ontario Nurses’ Association in their challenge to Directive 5, which restricted access to N95 masks in health care. He also served as a paid legal expert for the Elementary Teachers’ Federation of Ontario in its efforts to make schools safer in Ontario.
A version of this article first appeared on Medscape.com.
The study’s senior author is John Conly, MD, an infectious disease specialist and professor at the University of Calgary (Alta.), and Alberta Health Services. The findings are not consistent with those of many other studies on this topic.
Commenting about Dr. Conly’s study, Eric Topol, MD, editor-in-chief of Medscape, wrote: “It’s woefully underpowered but ruled out a doubling of hazard for use of medical masks.”
The study, which was partially funded by the World Health Organization, was published online in Annals of Internal Medicine.
This is not the first time that Dr. Conly, who also advises the WHO, has been the subject of controversy. He previously denied that COVID-19 is airborne – a position that is contradicted by strong evidence. In 2021, Dr. Conly made headlines with his controversial claim that N95 respirators can cause harms, including oxygen depletion and carbon dioxide retention.
A detailed examination by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, Minneapolis, pointed out numerous scientific flaws in the study, including inconsistent use of both types of masks. The study also examined health care workers in four very different countries (Canada, Israel, Egypt, and Pakistan) during different periods of the pandemic, which may have affected the results. Furthermore, the study did not account for vaccination status and lacked a control group. CIDRAP receives funding from 3M, which makes N95 respirators.
In a commentary published alongside the study, Roger Chou, MD, professor of medicine at Oregon Health & Science University, Portland, said that the results were “not definitive,” with “a generous noninferiority threshold” that is actually “consistent with up to a relative 70% increased risk ... which may be unacceptable to many health workers.”
Lead study author Mark Loeb, MD, professor of infectious diseases at McMaster University, Hamilton, Ont., defended the findings. “The confidence intervals around this, that is, what the possible results could be if the trial was repeated many times, range from −2.5% to 4.9%,” he told this news organization. “This means that the risk of a COVID-19 infection in those using the medical masks could have ranged from anywhere from 2.5% reduction in risk to a 4.9% increase in risk. Readers and policy makers can decide for themselves about this.”
“There is no point continuing to run underpowered, poorly designed studies that are designed to confirm existing biases,” Raina MacIntyre, PhD, professor of global biosecurity and head of the Biosecurity Program at the Kirby Institute, Sydney, said in an interview. “The new study in Annals of Internal Medicine is entirely consistent with our finding that to prevent infection, you need an N95, and it needs to be worn throughout the whole shift. A surgical mask and intermittent use of N95 are equally ineffective. This should not surprise anyone, given a surgical mask is not designed as respiratory protection but is designed to prevent splash or spray of liquid on the face. Only a respirator is designed as respiratory protection through both the seal around the face and the filter of the face piece to prevent inhalation of virus laden aerosols, but you need to wear it continually in a high-risk environment like a hospital.”
“It makes zero sense to do a randomized trial on something you can measure directly,” said Kimberly Prather, PhD, an atmospheric chemist, professor, and director of the NSF Center for Aerosol Impacts on Chemistry of the Environment at the University of California, San Diego. “In fact, many studies have shown aerosols leaking out of surgical masks. Surgical masks are designed to block large spray droplets. Aerosols (0.5-3 mcm), which have been shown to contain infectious SARS-CoV-2 virus, travel with the air flow, and escape.”
“This study ... will be used to justify policies of supplying health care workers, and perhaps patients and visitors, too, with inadequate protection,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford (England), told this news organization.
“These authors have been pushing back against treating COVID as airborne for 3 years,” David Fisman, MD, an epidemiologist and infectious disease specialist at the University of Toronto, said in an interview. “So, you’ll see these folks brandishing this very flawed trial to justify continuing the infection control practices that have been so disastrous throughout the pandemic.”
The study was funded by the World Health Organization, the Canadian Institutes of Health Research, and the Juravinski Research Institute. Dr. Conly reported receiving grants from the Canadian Institutes for Health Research, Pfizer, and the WHO. Dr. Chou disclosed being a methodologist for WHO guidelines on infection prevention and control measures for COVID-19. Dr. Loeb disclosed payment for expert testimony on personal protective equipment from the government of Manitoba and the Peel District School Board. Dr. MacIntyre has led a large body of research on masks and respirators in health workers, including four randomized clinical trials. She is the author of a book, “Dark Winter: An insider’s guide to pandemics and biosecurity” (Syndey: NewSouth Publishing, 2022), which covers the history and politics of the controversies around N95 and masks. Dr. Prather reported no disclosures. Dr. Greenhalgh is a member of Independent SAGE and an unpaid adviser to the philanthropic fund Balvi. Dr. Fisman has served as a paid legal expert for the Ontario Nurses’ Association in their challenge to Directive 5, which restricted access to N95 masks in health care. He also served as a paid legal expert for the Elementary Teachers’ Federation of Ontario in its efforts to make schools safer in Ontario.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Will a one-dose drug mean the end of sleeping sickness?
A single dose of oral acoziborole resulted in a greater than 95% cure or probable cure rate for human African trypanosomiasis (HAT), also known as sleeping sickness, according to results from a clinical trial testing a one-dose experimental drug.
The drug has “the potential to revolutionize treatment” for the disease, which remains endemic in sub-Saharan Africa, said Antoine Tarral, MD, head of the human African trypanosomiasis clinical program at the Drugs for Neglected Diseases initiative, based in Geneva, and senior author of the study, in a press release.
he told this news organization. “It’s the first drug we can use without hospitalization. ... All the previous medications needed hospitalization, and therefore we could not treat the population early before they started expressing symptoms.”
The World Health Organization “has been working for decades for such a possibility to implement a new strategy for this disease,” Dr. Tarral said.
Current (2019) WHO guidelines recommend oral fexinidazole as first-line treatment for any stage of the disease. The 10-day course often requires hospitalization and skilled staff. Previous recommendations required disease-staging with cerebrospinal fluid (CSF) sampling and 7 days of intramuscular pentamidine for early-stage disease or nifurtimox-eflornithine combination therapy (NECT) with hospitalization for late-stage disease.
By contrast, acoziborole, which was codeveloped by the DND initiative and Sanofi, “is administered in a single dose and is effective across every stage of the disease, thereby eliminating the many barriers currently in place for people most vulnerable to the diseases, such as invasive treatments and long travel distances to a hospital or clinic, and opening the door to screen-and-treat approaches at the village level,” Dr. Tarral said in the statement.
“Today, and in the future, we will have less and less support to do this long and costly diagnostic process and treatment in the hospital,” he said in an interview. “This development means we can go for a simple test and a simple treatment, which means we can meet the WHO 2030 goal for ending transmission of this disease.”
Results from the multicenter, prospective, open-label, single-arm, noncomparative, phase 2/3 study were published in The Lancet.
Pragmatic study design
Sleeping sickness is caused by Trypanosoma brucei gambiense (gambiense HAT). It is transmitted by the tsetse fly and mostly fatal when left untreated.
The study enrolled 208 adults and adolescents (167 with late-stage, and 41 with early-stage or intermediate-stage disease) from 10 hospitals in the Democratic Republic of the Congo and Guinea. All patients were treated with acoziborole 960 mg – an unusual study design.
“Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging,” the authors wrote. “Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group.”
After 18 months of follow-up, treatment success, defined as absence of trypanosomes and less than 20 white blood cells per mcL of CSF, occurred in 159 (95.2%) of the late-stage patients, and 100% of the early- and intermediate-stage patients, “which was similar to the estimated historical results for NECT,” the authors noted.
Serious treatment-emergent adverse events were reported in 21 (10%) of patients, “but none of these events were considered drug-related,” they added.
The DND initiative and the WHO are currently nearing completion of a much larger, double-blind, placebo-controlled trial of acoziborole to “increase the safety database,” Dr. Tarral explained.
“Purists will say that acoziborole has not been evaluated according to current standards, because the study was not a randomized trial, there was no control group, and the number of participants was small,” said Jacques Pépin, MD, from the University of Sherbrooke (Que.), in a linked commentary.
“But these were difficult challenges to overcome, considering the drastic reduction in the number of patients with HAT and dispersion over a vast territory, particularly in the Democratic Republic of the Congo. For these reasons, the authors took a pragmatic approach instead,” he wrote.
A potential new tool for eradication of sleeping sickness
“This is really an exciting development, which will be useful in the drive for eradication/interruption of transmission of this disease,” Dr. Pépin told this news organization.
Dr. Pépin treated around 1,000 trypanosomiasis patients during an outbreak in Zaire in the early 1980s. Because the asymptomatic incubation period for the disease can be several months or even years, “the core strategy for controlling the disease is active screening,” he said in an interview.
“You try to convince the whole population of endemic villages to show up on a given day, and then you have a mobile team of nurses who examine everybody, trying to find those with early trypanosomiasis. This includes physical examination for lymph nodes in the neck, but also a blood test whose results are available within minutes,” he said.
“Until now, these persons with a positive serology would undergo additional and labor-intensive examinations of blood to try to find trypanosomes and prove that they have the disease. So far those with a positive serology and negative parasitological assays (‘serological suspects’) were left untreated, because the treatments were toxic and cumbersome, and because a substantial but unknown proportion of these ‘suspects’ just have a false positive of their serological test, without having the disease,” Dr. Pépin said.
“Now with acoziborole, which seems to have little serious toxicity ... and can be given as a single-dose oral med, it might be reasonable to treat the ‘serological suspects,’ ” he said.
“Take it one step further, it might be possible to do the serological test only and treat all individuals with a positive serology without bothering to do parasitological assays. This is what they call ‘test-and-treat’ strategy. It would make sense, provided that we are sure that the drug is very well tolerated.”
Dr. Pépin added that he is “just slightly worried” about three patients described in the paper who had psychiatric adverse events 3 months after treatment. “If that happens to patients who indeed have trypanosomiasis, that’s a reasonable price to pay considering the toxicity of other drugs,” he said. “If that happens to serological suspects, many of whom don’t have any disease, this becomes a preoccupation.”
But Dr. Tarral said, “We have no indication that the drug can provoke psychiatric symptoms. In fact, the psychiatric symptoms did not emerge – they re-emerged after 3 months due to some patients’ refusal to be followed up.”
“We included patients in very advanced stages of the disease, and these symptoms are considered disease sequelae,” Dr. Tarral said. “The majority of patients who have such psychiatric symptoms need follow-up after treatment. If not, they can relapse very early. There were a lot of patients who had such symptoms and the investigators proposed they should be followed by a psychiatrist and some of them refused. And due to that only three of our patients had this relapse, and they were cured after psychiatric support.”
The study was funded through the DND initiative and was supported by grants from the Bill & Melinda Gates Foundation; UK Aid; the Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; the Swiss Agency for Development and Cooperation; Médecins Sans Frontières; the Dutch Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the Stavros Niarchos Foundation; the Spanish Agency for International Development Cooperation; and the Banco Bilbao Vizcaya Argentaria Foundation.
A number of study investigators, including Dr. Tarral, report employment at the DND initiative. Other investigators report fees from the DND initiative for the statistical report, consulting fees from CEMAG, D&A Pharma, Inventiva, and OT4B Pharma. The Swiss Tropical and Public Health Institute acted as a service provider for the DND initiative by monitoring the study sites. Dr. Pépin declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A single dose of oral acoziborole resulted in a greater than 95% cure or probable cure rate for human African trypanosomiasis (HAT), also known as sleeping sickness, according to results from a clinical trial testing a one-dose experimental drug.
The drug has “the potential to revolutionize treatment” for the disease, which remains endemic in sub-Saharan Africa, said Antoine Tarral, MD, head of the human African trypanosomiasis clinical program at the Drugs for Neglected Diseases initiative, based in Geneva, and senior author of the study, in a press release.
he told this news organization. “It’s the first drug we can use without hospitalization. ... All the previous medications needed hospitalization, and therefore we could not treat the population early before they started expressing symptoms.”
The World Health Organization “has been working for decades for such a possibility to implement a new strategy for this disease,” Dr. Tarral said.
Current (2019) WHO guidelines recommend oral fexinidazole as first-line treatment for any stage of the disease. The 10-day course often requires hospitalization and skilled staff. Previous recommendations required disease-staging with cerebrospinal fluid (CSF) sampling and 7 days of intramuscular pentamidine for early-stage disease or nifurtimox-eflornithine combination therapy (NECT) with hospitalization for late-stage disease.
By contrast, acoziborole, which was codeveloped by the DND initiative and Sanofi, “is administered in a single dose and is effective across every stage of the disease, thereby eliminating the many barriers currently in place for people most vulnerable to the diseases, such as invasive treatments and long travel distances to a hospital or clinic, and opening the door to screen-and-treat approaches at the village level,” Dr. Tarral said in the statement.
“Today, and in the future, we will have less and less support to do this long and costly diagnostic process and treatment in the hospital,” he said in an interview. “This development means we can go for a simple test and a simple treatment, which means we can meet the WHO 2030 goal for ending transmission of this disease.”
Results from the multicenter, prospective, open-label, single-arm, noncomparative, phase 2/3 study were published in The Lancet.
Pragmatic study design
Sleeping sickness is caused by Trypanosoma brucei gambiense (gambiense HAT). It is transmitted by the tsetse fly and mostly fatal when left untreated.
The study enrolled 208 adults and adolescents (167 with late-stage, and 41 with early-stage or intermediate-stage disease) from 10 hospitals in the Democratic Republic of the Congo and Guinea. All patients were treated with acoziborole 960 mg – an unusual study design.
“Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging,” the authors wrote. “Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group.”
After 18 months of follow-up, treatment success, defined as absence of trypanosomes and less than 20 white blood cells per mcL of CSF, occurred in 159 (95.2%) of the late-stage patients, and 100% of the early- and intermediate-stage patients, “which was similar to the estimated historical results for NECT,” the authors noted.
Serious treatment-emergent adverse events were reported in 21 (10%) of patients, “but none of these events were considered drug-related,” they added.
The DND initiative and the WHO are currently nearing completion of a much larger, double-blind, placebo-controlled trial of acoziborole to “increase the safety database,” Dr. Tarral explained.
“Purists will say that acoziborole has not been evaluated according to current standards, because the study was not a randomized trial, there was no control group, and the number of participants was small,” said Jacques Pépin, MD, from the University of Sherbrooke (Que.), in a linked commentary.
“But these were difficult challenges to overcome, considering the drastic reduction in the number of patients with HAT and dispersion over a vast territory, particularly in the Democratic Republic of the Congo. For these reasons, the authors took a pragmatic approach instead,” he wrote.
A potential new tool for eradication of sleeping sickness
“This is really an exciting development, which will be useful in the drive for eradication/interruption of transmission of this disease,” Dr. Pépin told this news organization.
Dr. Pépin treated around 1,000 trypanosomiasis patients during an outbreak in Zaire in the early 1980s. Because the asymptomatic incubation period for the disease can be several months or even years, “the core strategy for controlling the disease is active screening,” he said in an interview.
“You try to convince the whole population of endemic villages to show up on a given day, and then you have a mobile team of nurses who examine everybody, trying to find those with early trypanosomiasis. This includes physical examination for lymph nodes in the neck, but also a blood test whose results are available within minutes,” he said.
“Until now, these persons with a positive serology would undergo additional and labor-intensive examinations of blood to try to find trypanosomes and prove that they have the disease. So far those with a positive serology and negative parasitological assays (‘serological suspects’) were left untreated, because the treatments were toxic and cumbersome, and because a substantial but unknown proportion of these ‘suspects’ just have a false positive of their serological test, without having the disease,” Dr. Pépin said.
“Now with acoziborole, which seems to have little serious toxicity ... and can be given as a single-dose oral med, it might be reasonable to treat the ‘serological suspects,’ ” he said.
“Take it one step further, it might be possible to do the serological test only and treat all individuals with a positive serology without bothering to do parasitological assays. This is what they call ‘test-and-treat’ strategy. It would make sense, provided that we are sure that the drug is very well tolerated.”
Dr. Pépin added that he is “just slightly worried” about three patients described in the paper who had psychiatric adverse events 3 months after treatment. “If that happens to patients who indeed have trypanosomiasis, that’s a reasonable price to pay considering the toxicity of other drugs,” he said. “If that happens to serological suspects, many of whom don’t have any disease, this becomes a preoccupation.”
But Dr. Tarral said, “We have no indication that the drug can provoke psychiatric symptoms. In fact, the psychiatric symptoms did not emerge – they re-emerged after 3 months due to some patients’ refusal to be followed up.”
“We included patients in very advanced stages of the disease, and these symptoms are considered disease sequelae,” Dr. Tarral said. “The majority of patients who have such psychiatric symptoms need follow-up after treatment. If not, they can relapse very early. There were a lot of patients who had such symptoms and the investigators proposed they should be followed by a psychiatrist and some of them refused. And due to that only three of our patients had this relapse, and they were cured after psychiatric support.”
The study was funded through the DND initiative and was supported by grants from the Bill & Melinda Gates Foundation; UK Aid; the Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; the Swiss Agency for Development and Cooperation; Médecins Sans Frontières; the Dutch Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the Stavros Niarchos Foundation; the Spanish Agency for International Development Cooperation; and the Banco Bilbao Vizcaya Argentaria Foundation.
A number of study investigators, including Dr. Tarral, report employment at the DND initiative. Other investigators report fees from the DND initiative for the statistical report, consulting fees from CEMAG, D&A Pharma, Inventiva, and OT4B Pharma. The Swiss Tropical and Public Health Institute acted as a service provider for the DND initiative by monitoring the study sites. Dr. Pépin declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A single dose of oral acoziborole resulted in a greater than 95% cure or probable cure rate for human African trypanosomiasis (HAT), also known as sleeping sickness, according to results from a clinical trial testing a one-dose experimental drug.
The drug has “the potential to revolutionize treatment” for the disease, which remains endemic in sub-Saharan Africa, said Antoine Tarral, MD, head of the human African trypanosomiasis clinical program at the Drugs for Neglected Diseases initiative, based in Geneva, and senior author of the study, in a press release.
he told this news organization. “It’s the first drug we can use without hospitalization. ... All the previous medications needed hospitalization, and therefore we could not treat the population early before they started expressing symptoms.”
The World Health Organization “has been working for decades for such a possibility to implement a new strategy for this disease,” Dr. Tarral said.
Current (2019) WHO guidelines recommend oral fexinidazole as first-line treatment for any stage of the disease. The 10-day course often requires hospitalization and skilled staff. Previous recommendations required disease-staging with cerebrospinal fluid (CSF) sampling and 7 days of intramuscular pentamidine for early-stage disease or nifurtimox-eflornithine combination therapy (NECT) with hospitalization for late-stage disease.
By contrast, acoziborole, which was codeveloped by the DND initiative and Sanofi, “is administered in a single dose and is effective across every stage of the disease, thereby eliminating the many barriers currently in place for people most vulnerable to the diseases, such as invasive treatments and long travel distances to a hospital or clinic, and opening the door to screen-and-treat approaches at the village level,” Dr. Tarral said in the statement.
“Today, and in the future, we will have less and less support to do this long and costly diagnostic process and treatment in the hospital,” he said in an interview. “This development means we can go for a simple test and a simple treatment, which means we can meet the WHO 2030 goal for ending transmission of this disease.”
Results from the multicenter, prospective, open-label, single-arm, noncomparative, phase 2/3 study were published in The Lancet.
Pragmatic study design
Sleeping sickness is caused by Trypanosoma brucei gambiense (gambiense HAT). It is transmitted by the tsetse fly and mostly fatal when left untreated.
The study enrolled 208 adults and adolescents (167 with late-stage, and 41 with early-stage or intermediate-stage disease) from 10 hospitals in the Democratic Republic of the Congo and Guinea. All patients were treated with acoziborole 960 mg – an unusual study design.
“Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging,” the authors wrote. “Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group.”
After 18 months of follow-up, treatment success, defined as absence of trypanosomes and less than 20 white blood cells per mcL of CSF, occurred in 159 (95.2%) of the late-stage patients, and 100% of the early- and intermediate-stage patients, “which was similar to the estimated historical results for NECT,” the authors noted.
Serious treatment-emergent adverse events were reported in 21 (10%) of patients, “but none of these events were considered drug-related,” they added.
The DND initiative and the WHO are currently nearing completion of a much larger, double-blind, placebo-controlled trial of acoziborole to “increase the safety database,” Dr. Tarral explained.
“Purists will say that acoziborole has not been evaluated according to current standards, because the study was not a randomized trial, there was no control group, and the number of participants was small,” said Jacques Pépin, MD, from the University of Sherbrooke (Que.), in a linked commentary.
“But these were difficult challenges to overcome, considering the drastic reduction in the number of patients with HAT and dispersion over a vast territory, particularly in the Democratic Republic of the Congo. For these reasons, the authors took a pragmatic approach instead,” he wrote.
A potential new tool for eradication of sleeping sickness
“This is really an exciting development, which will be useful in the drive for eradication/interruption of transmission of this disease,” Dr. Pépin told this news organization.
Dr. Pépin treated around 1,000 trypanosomiasis patients during an outbreak in Zaire in the early 1980s. Because the asymptomatic incubation period for the disease can be several months or even years, “the core strategy for controlling the disease is active screening,” he said in an interview.
“You try to convince the whole population of endemic villages to show up on a given day, and then you have a mobile team of nurses who examine everybody, trying to find those with early trypanosomiasis. This includes physical examination for lymph nodes in the neck, but also a blood test whose results are available within minutes,” he said.
“Until now, these persons with a positive serology would undergo additional and labor-intensive examinations of blood to try to find trypanosomes and prove that they have the disease. So far those with a positive serology and negative parasitological assays (‘serological suspects’) were left untreated, because the treatments were toxic and cumbersome, and because a substantial but unknown proportion of these ‘suspects’ just have a false positive of their serological test, without having the disease,” Dr. Pépin said.
“Now with acoziborole, which seems to have little serious toxicity ... and can be given as a single-dose oral med, it might be reasonable to treat the ‘serological suspects,’ ” he said.
“Take it one step further, it might be possible to do the serological test only and treat all individuals with a positive serology without bothering to do parasitological assays. This is what they call ‘test-and-treat’ strategy. It would make sense, provided that we are sure that the drug is very well tolerated.”
Dr. Pépin added that he is “just slightly worried” about three patients described in the paper who had psychiatric adverse events 3 months after treatment. “If that happens to patients who indeed have trypanosomiasis, that’s a reasonable price to pay considering the toxicity of other drugs,” he said. “If that happens to serological suspects, many of whom don’t have any disease, this becomes a preoccupation.”
But Dr. Tarral said, “We have no indication that the drug can provoke psychiatric symptoms. In fact, the psychiatric symptoms did not emerge – they re-emerged after 3 months due to some patients’ refusal to be followed up.”
“We included patients in very advanced stages of the disease, and these symptoms are considered disease sequelae,” Dr. Tarral said. “The majority of patients who have such psychiatric symptoms need follow-up after treatment. If not, they can relapse very early. There were a lot of patients who had such symptoms and the investigators proposed they should be followed by a psychiatrist and some of them refused. And due to that only three of our patients had this relapse, and they were cured after psychiatric support.”
The study was funded through the DND initiative and was supported by grants from the Bill & Melinda Gates Foundation; UK Aid; the Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, Germany; the Swiss Agency for Development and Cooperation; Médecins Sans Frontières; the Dutch Ministry of Foreign Affairs; the Norwegian Agency for Development Cooperation; the Stavros Niarchos Foundation; the Spanish Agency for International Development Cooperation; and the Banco Bilbao Vizcaya Argentaria Foundation.
A number of study investigators, including Dr. Tarral, report employment at the DND initiative. Other investigators report fees from the DND initiative for the statistical report, consulting fees from CEMAG, D&A Pharma, Inventiva, and OT4B Pharma. The Swiss Tropical and Public Health Institute acted as a service provider for the DND initiative by monitoring the study sites. Dr. Pépin declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Study affirms shorter regimens for drug-resistant tuberculosis
Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.
The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.
The study was published in The Lancet.
The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.
The study’s first stage, STREAM stage 1, showed that The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
Seeking shorter treatment for better outcomes
STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).
The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.
The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.
For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).
Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).
For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.
In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.
Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.
Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.
The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.
“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.
“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.
Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).
“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
‘A revolution in MDR tuberculosis’
“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.
Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.
The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.
However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”
The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.
A version of this article first appeared on Medscape.com.
Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.
The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.
The study was published in The Lancet.
The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.
The study’s first stage, STREAM stage 1, showed that The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
Seeking shorter treatment for better outcomes
STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).
The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.
The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.
For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).
Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).
For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.
In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.
Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.
Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.
The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.
“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.
“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.
Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).
“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
‘A revolution in MDR tuberculosis’
“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.
Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.
The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.
However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”
The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.
A version of this article first appeared on Medscape.com.
Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.
The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.
The study was published in The Lancet.
The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.
The study’s first stage, STREAM stage 1, showed that The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
Seeking shorter treatment for better outcomes
STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).
The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.
The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.
For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).
Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).
For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.
In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.
Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.
Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.
The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.
“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.
“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.
Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).
“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
‘A revolution in MDR tuberculosis’
“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.
Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.
The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.
However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”
The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.
A version of this article first appeared on Medscape.com.
New genetic variant linked to maturity-onset diabetes of the young
A newly discovered genetic variant that is associated with type 2 diabetes (T2D) is responsible for almost 7% of all diabetes cases in Greenland, according to a whole-genome sequencing analysis of 448 Greenlandic Inuit individuals.
The variant, identified as c.1108G>T, “has the largest population impact of any previously reported variant” within the HNF1A gene – a gene that can cause maturity-onset diabetes of the young (MODY), reported senior author Torben Hansen, MD, PhD, of the University of Copenhagen, and colleagues in The Lancet Regional Health–Europe. The c.1108G>T variant does not cause MODY, but other variants within the HNF1A gene do. However, carriers of this variant, which is present in 1.9% of the Greenlandic Inuit population and has not been found elsewhere, have normal insulin sensitivity, but decreased beta-cell function and a more than fourfold risk of developing type 2 diabetes. “This adds to a previous discovery that about 11% of all diabetes in Greenlandic Inuit is explained by a mutation in the TBC1D4 variant,” Dr. Hansen told this publication. “Thus 1 in 5 patients diagnosed with type 2 diabetes in Greenland have a specific mutation explaining their diabetes. In European populations only about 1%-2% of patients diagnosed with type 2 diabetes have a known genetic etiology.”
The finding “provides new avenues to subgroup patients, detect diabetes in family members, and pursue precision treatment trials,” noted the authors, although they acknowledged that treatment choices for individuals with this variant still need to be explored. “We know from HNF1A-mutation carriers with European ancestry that they benefit from sulfonylurea treatment,” said Dr. Hansen. “However, we have not yet done treatment studies in Inuit.” The investigators noted that “it is not always the case that variants in HNF1A result in an increased insulin secretory response to sulfonylurea. ... Whether carriers of the c.1108G>T variant could benefit from treatment with sulfonylurea should be pursued within the context of a randomized clinical trial establishing both short- and long-term efficacy of sulfonylurea in these patients.”
A total of 4,497 study participants were randomly sampled from two cross-sectional cohorts in an adult Greenlandic population health survey. Among 448 participants who had whole genome sequencing, 14 known MODY genes were screened for both previously identified as well as novel variants. This identified the c.1108G>T variant, which was then genotyped in the full cohort in order to estimate an allele frequency of 1.3% in the general Greenlandic population, and 1.9% in the Inuit component. The variant was not found in genome sequences of other populations.
The researchers then tested the association of the variant with T2D and showed strong association with T2D (odds ratio, 4.35) and higher hemoglobin A1c levels.
“This is very well-conducted and exciting research that highlights the importance of studying the genetics of diverse populations,” said Miriam Udler, MD, PhD, director of the Massachusetts General Diabetes Genetics Clinic, and assistant professor at Harvard University, both in Boston. “This manuscript builds on prior work from the researchers identifying another genetic variant specific to the Greenlandic Inuit population in the gene TBC1D4,” she added. “About 3.8% of people in this population carry two copies of the TBC1D4 variant and have about a 10-fold increased risk of diabetes. Together the two variants affect 18% of Greenlanders with diabetes.”
With its fourfold increased risk of diabetes, the new variant falls into “an ever-growing category” of “intermediate risk” genetic variants, explained Dr. Udler – “meaning that they have a large impact on diabetes risk, but cannot fully predict whether someone will get diabetes. The contribution of additional risk factors is particularly important for ‘intermediate risk’ genetic variants,” she added. “Thus, clinically, we can tell patients who have variants such as HNF1A c.1108>T that they are at substantial increased risk of diabetes, but that many will not develop diabetes. And for those who do develop diabetes, we are not yet able to advise on particular therapeutic strategies.”
Still, she emphasized, the importance of studying diverse populations with specific genetic risk factors is the end-goal of precision medicine. “An active area of research is determining whether and how to return such information about ‘intermediate risk’ variants to patients who get clinical genetic testing for diabetes, since typically only variants that are very high risk ... are returned in clinical testing reports.” Dr. Udler added that “many more such “intermediate risk’ variants likely exist in all populations, but have yet to be characterized because they are less common than HNF1A c.1108>T; however, ongoing worldwide efforts to increase the sample sizes of human genetic studies will facilitate such discovery.”
The study was funded by Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen’s Foundation. Dr. Hansen and Dr. Udler had no disclosures.
A newly discovered genetic variant that is associated with type 2 diabetes (T2D) is responsible for almost 7% of all diabetes cases in Greenland, according to a whole-genome sequencing analysis of 448 Greenlandic Inuit individuals.
The variant, identified as c.1108G>T, “has the largest population impact of any previously reported variant” within the HNF1A gene – a gene that can cause maturity-onset diabetes of the young (MODY), reported senior author Torben Hansen, MD, PhD, of the University of Copenhagen, and colleagues in The Lancet Regional Health–Europe. The c.1108G>T variant does not cause MODY, but other variants within the HNF1A gene do. However, carriers of this variant, which is present in 1.9% of the Greenlandic Inuit population and has not been found elsewhere, have normal insulin sensitivity, but decreased beta-cell function and a more than fourfold risk of developing type 2 diabetes. “This adds to a previous discovery that about 11% of all diabetes in Greenlandic Inuit is explained by a mutation in the TBC1D4 variant,” Dr. Hansen told this publication. “Thus 1 in 5 patients diagnosed with type 2 diabetes in Greenland have a specific mutation explaining their diabetes. In European populations only about 1%-2% of patients diagnosed with type 2 diabetes have a known genetic etiology.”
The finding “provides new avenues to subgroup patients, detect diabetes in family members, and pursue precision treatment trials,” noted the authors, although they acknowledged that treatment choices for individuals with this variant still need to be explored. “We know from HNF1A-mutation carriers with European ancestry that they benefit from sulfonylurea treatment,” said Dr. Hansen. “However, we have not yet done treatment studies in Inuit.” The investigators noted that “it is not always the case that variants in HNF1A result in an increased insulin secretory response to sulfonylurea. ... Whether carriers of the c.1108G>T variant could benefit from treatment with sulfonylurea should be pursued within the context of a randomized clinical trial establishing both short- and long-term efficacy of sulfonylurea in these patients.”
A total of 4,497 study participants were randomly sampled from two cross-sectional cohorts in an adult Greenlandic population health survey. Among 448 participants who had whole genome sequencing, 14 known MODY genes were screened for both previously identified as well as novel variants. This identified the c.1108G>T variant, which was then genotyped in the full cohort in order to estimate an allele frequency of 1.3% in the general Greenlandic population, and 1.9% in the Inuit component. The variant was not found in genome sequences of other populations.
The researchers then tested the association of the variant with T2D and showed strong association with T2D (odds ratio, 4.35) and higher hemoglobin A1c levels.
“This is very well-conducted and exciting research that highlights the importance of studying the genetics of diverse populations,” said Miriam Udler, MD, PhD, director of the Massachusetts General Diabetes Genetics Clinic, and assistant professor at Harvard University, both in Boston. “This manuscript builds on prior work from the researchers identifying another genetic variant specific to the Greenlandic Inuit population in the gene TBC1D4,” she added. “About 3.8% of people in this population carry two copies of the TBC1D4 variant and have about a 10-fold increased risk of diabetes. Together the two variants affect 18% of Greenlanders with diabetes.”
With its fourfold increased risk of diabetes, the new variant falls into “an ever-growing category” of “intermediate risk” genetic variants, explained Dr. Udler – “meaning that they have a large impact on diabetes risk, but cannot fully predict whether someone will get diabetes. The contribution of additional risk factors is particularly important for ‘intermediate risk’ genetic variants,” she added. “Thus, clinically, we can tell patients who have variants such as HNF1A c.1108>T that they are at substantial increased risk of diabetes, but that many will not develop diabetes. And for those who do develop diabetes, we are not yet able to advise on particular therapeutic strategies.”
Still, she emphasized, the importance of studying diverse populations with specific genetic risk factors is the end-goal of precision medicine. “An active area of research is determining whether and how to return such information about ‘intermediate risk’ variants to patients who get clinical genetic testing for diabetes, since typically only variants that are very high risk ... are returned in clinical testing reports.” Dr. Udler added that “many more such “intermediate risk’ variants likely exist in all populations, but have yet to be characterized because they are less common than HNF1A c.1108>T; however, ongoing worldwide efforts to increase the sample sizes of human genetic studies will facilitate such discovery.”
The study was funded by Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen’s Foundation. Dr. Hansen and Dr. Udler had no disclosures.
A newly discovered genetic variant that is associated with type 2 diabetes (T2D) is responsible for almost 7% of all diabetes cases in Greenland, according to a whole-genome sequencing analysis of 448 Greenlandic Inuit individuals.
The variant, identified as c.1108G>T, “has the largest population impact of any previously reported variant” within the HNF1A gene – a gene that can cause maturity-onset diabetes of the young (MODY), reported senior author Torben Hansen, MD, PhD, of the University of Copenhagen, and colleagues in The Lancet Regional Health–Europe. The c.1108G>T variant does not cause MODY, but other variants within the HNF1A gene do. However, carriers of this variant, which is present in 1.9% of the Greenlandic Inuit population and has not been found elsewhere, have normal insulin sensitivity, but decreased beta-cell function and a more than fourfold risk of developing type 2 diabetes. “This adds to a previous discovery that about 11% of all diabetes in Greenlandic Inuit is explained by a mutation in the TBC1D4 variant,” Dr. Hansen told this publication. “Thus 1 in 5 patients diagnosed with type 2 diabetes in Greenland have a specific mutation explaining their diabetes. In European populations only about 1%-2% of patients diagnosed with type 2 diabetes have a known genetic etiology.”
The finding “provides new avenues to subgroup patients, detect diabetes in family members, and pursue precision treatment trials,” noted the authors, although they acknowledged that treatment choices for individuals with this variant still need to be explored. “We know from HNF1A-mutation carriers with European ancestry that they benefit from sulfonylurea treatment,” said Dr. Hansen. “However, we have not yet done treatment studies in Inuit.” The investigators noted that “it is not always the case that variants in HNF1A result in an increased insulin secretory response to sulfonylurea. ... Whether carriers of the c.1108G>T variant could benefit from treatment with sulfonylurea should be pursued within the context of a randomized clinical trial establishing both short- and long-term efficacy of sulfonylurea in these patients.”
A total of 4,497 study participants were randomly sampled from two cross-sectional cohorts in an adult Greenlandic population health survey. Among 448 participants who had whole genome sequencing, 14 known MODY genes were screened for both previously identified as well as novel variants. This identified the c.1108G>T variant, which was then genotyped in the full cohort in order to estimate an allele frequency of 1.3% in the general Greenlandic population, and 1.9% in the Inuit component. The variant was not found in genome sequences of other populations.
The researchers then tested the association of the variant with T2D and showed strong association with T2D (odds ratio, 4.35) and higher hemoglobin A1c levels.
“This is very well-conducted and exciting research that highlights the importance of studying the genetics of diverse populations,” said Miriam Udler, MD, PhD, director of the Massachusetts General Diabetes Genetics Clinic, and assistant professor at Harvard University, both in Boston. “This manuscript builds on prior work from the researchers identifying another genetic variant specific to the Greenlandic Inuit population in the gene TBC1D4,” she added. “About 3.8% of people in this population carry two copies of the TBC1D4 variant and have about a 10-fold increased risk of diabetes. Together the two variants affect 18% of Greenlanders with diabetes.”
With its fourfold increased risk of diabetes, the new variant falls into “an ever-growing category” of “intermediate risk” genetic variants, explained Dr. Udler – “meaning that they have a large impact on diabetes risk, but cannot fully predict whether someone will get diabetes. The contribution of additional risk factors is particularly important for ‘intermediate risk’ genetic variants,” she added. “Thus, clinically, we can tell patients who have variants such as HNF1A c.1108>T that they are at substantial increased risk of diabetes, but that many will not develop diabetes. And for those who do develop diabetes, we are not yet able to advise on particular therapeutic strategies.”
Still, she emphasized, the importance of studying diverse populations with specific genetic risk factors is the end-goal of precision medicine. “An active area of research is determining whether and how to return such information about ‘intermediate risk’ variants to patients who get clinical genetic testing for diabetes, since typically only variants that are very high risk ... are returned in clinical testing reports.” Dr. Udler added that “many more such “intermediate risk’ variants likely exist in all populations, but have yet to be characterized because they are less common than HNF1A c.1108>T; however, ongoing worldwide efforts to increase the sample sizes of human genetic studies will facilitate such discovery.”
The study was funded by Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen’s Foundation. Dr. Hansen and Dr. Udler had no disclosures.
FROM THE LANCET REGIONAL HEALTH–EUROPE
Study finds chronic jet lag–like body clocks in people with HIV
, according to findings that suggest both a possible mechanism for increased comorbidities in PLWH and potential solutions.
“It is very well known that sleep problems are common in people living with HIV, and many different reasons for this have been proposed,” coauthor Malcolm von Schantz, PhD, professor of chronobiology at Northumbria University in Newcastle upon Tyne, England, said in an interview. “But the novelty of our findings is the observation of delayed circadian rhythms.”
The mistimed circadian phase in PLWH is linked to later sleep onset and earlier waking and has “important potential implications” for the health and well-being of PLWH, wrote senior author Karine Scheuermaier, MD, from the University of the Witwatersrand, in Johannesburg, South Africa, and coauthors.
Until now, research on sleep in HIV has focused primarily on its homeostatic components, such as sleep duration and staging, rather than on circadian-related aspects, they noted.
“If the lifestyle‐independent circadian misalignment observed in the current study is confirmed to be a constant feature of chronic HIV infection, then it may be a mediator both of poorer sleep health and of poorer physical health in PLWH, which could potentially be alleviated through light therapy or chronobiotic medication or supplements,” they suggested.
HIV endemic in study population
The study analyzed a random sample of 187 participants (36 with HIV and 151 without) in the HAALSI (Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) study, which is part of the Agincourt Health and Socio-demographic Surveillance System.
The study population ranged in age from 45 to 93 years, with an average age of 60.6 years in the HIV-positive group and 68.2 years in the HIV-negative group. Demographic data, Pittsburgh Sleep Quality Index score, and valid actigraphy (measured with an accelerometer for 14 consecutive days) were available for 172 participants (18% with HIV). A subgroup of 51 participants (22% with HIV) also had valid dim light melatonin onset (DLMO) data, a sensitive measure of the internal circadian clock. DLMO was measured for a minimum of 5 consecutive days with hourly saliva sampling between 5 p.m. and 11 p.m. while sitting in a dimly lit room.
In 36 participants (16% with HIV) with both valid actigraphy and DLMO data, circadian phase angle of entrainment was calculated by subtracting DLMO time from habitual sleep-onset time obtained from actigraphy.
After adjustment for age and sex, the study found a slightly later sleep onset (adjusted average delay of 10 minutes), earlier awakening (adjusted average advance of 10 minutes), and shorter sleep duration in PLWH compared with HIV-negative participants.
At the same time, melatonin production in PLWH started more than an hour later on average than in HIV-negative participants, “with half of the HIV+ group having an earlier habitual sleep onset than DLMO time” the authors wrote. In a subgroup of 36 participants with both valid actigraphy and DLMO data, the median circadian phase angle of entrainment was smaller in PLWH (–6 minutes vs. +1 hour 25 minutes in the HIV-negative group).
“Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants,” they added.
Asynchrony between bedtime and circadian time
“Ideally, with this delayed timing of circadian phase, they should have delayed their sleep phase (sleep timing) by an equal amount to be sleeping at their optimal biological time,” Dr. Scheuermaier explained. “Their sleep onset was delayed by 12 minutes (statistically significant but biologically not that much) while their circadian phase was delayed by more than an hour.”
Possible consequences of a smaller phase angle of entrainment include difficulty in initiating and maintaining sleep, the authors wrote. “The shorter, potentially mistimed sleep relative to the endogenous circadian cycle observed in this study provides objectively measured evidence supporting the abundant previous subjective reports of poor sleep quality and insomnia in PLWH.”
They noted that a strength of their study is that participants were recruited from rural South Africa, where HIV prevalence is not confined to the so-called “high-risk” groups of gay men, other men who have sex with men, people who inject drugs, and sex workers.
“Behavioral factors associated with belonging to one or more of these groups would be strong potential confounders for studies of sleep and circadian phase,” they explained. “By contrast, in rural southern Africa, the epidemic has been less demographically discriminating ... There are no notable differences in lifestyle between the HIV– and HIV+ individuals in this study. The members of this aging population are mostly beyond retirement age, living quiet, rural lives supported by government remittances and subsistence farming.”
Direct evidence warrants further study
The study is “unique” in that it provides “the first direct evidence for potential circadian disturbances in PWLH,” agreed Peng Li, PhD, who was not involved in the study.
“The assessment of dim light melatonin onset in PLWH is a strength of the study; together with actigraphy-based sleep onset assessment, it provides a measure for the phase angle of entrainment,” said Dr. Li, who is research director of the medical biodynamics program, division of sleep and circadian disorders, Brigham and Women’s Hospital, Boston.
But actigraphy has limitations that affect the interpretation of the results, he told this news organization.
“Without the help of sleep diaries, low specificity in assessing sleep using actigraphy has been consistently reported,” he said. “The low specificity means a significant overestimation of sleep. This lowers the value of the reported sleep readouts and limits the validity of sleep onset estimation, especially considering that differences in sleep measures between the two groups are relatively small, compromising the clinical meaning.”
Additionally, he explained that it’s not clear whether sleep onset in the study participants was spontaneous or was “forced” to accommodate routines. “This is a limitation in field study as compared with in-lab studies,” he said.
Dr. Li also pointed to the small sample size and younger age of PLWH, suggesting the study might have benefited from a matched design. Finally, he said the study did not examine gender differences.
“In the general population, it is known that females usually have advanced circadian phase compared to males. ... More rigorous design and analyses based on sex/gender especially in this often-marginalized population are warranted to better inform HIV-specific or general clinical guidelines.”
The study was supported by the Academy of Medical Sciences. The authors did not mention any competing interests. Dr. Li reported grant support from the BrightFocus Foundation. The study is not directly related to this paper. He also receives grant support from the NIH through a Departmental Award, Harvard University Center for AIDS Research and a Pilot Project, HIV and Aging Research Consortium. The projects are on circadian disturbances and cognitive performance in PLWH.
A version of this article first appeared on Medscape.com.
, according to findings that suggest both a possible mechanism for increased comorbidities in PLWH and potential solutions.
“It is very well known that sleep problems are common in people living with HIV, and many different reasons for this have been proposed,” coauthor Malcolm von Schantz, PhD, professor of chronobiology at Northumbria University in Newcastle upon Tyne, England, said in an interview. “But the novelty of our findings is the observation of delayed circadian rhythms.”
The mistimed circadian phase in PLWH is linked to later sleep onset and earlier waking and has “important potential implications” for the health and well-being of PLWH, wrote senior author Karine Scheuermaier, MD, from the University of the Witwatersrand, in Johannesburg, South Africa, and coauthors.
Until now, research on sleep in HIV has focused primarily on its homeostatic components, such as sleep duration and staging, rather than on circadian-related aspects, they noted.
“If the lifestyle‐independent circadian misalignment observed in the current study is confirmed to be a constant feature of chronic HIV infection, then it may be a mediator both of poorer sleep health and of poorer physical health in PLWH, which could potentially be alleviated through light therapy or chronobiotic medication or supplements,” they suggested.
HIV endemic in study population
The study analyzed a random sample of 187 participants (36 with HIV and 151 without) in the HAALSI (Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) study, which is part of the Agincourt Health and Socio-demographic Surveillance System.
The study population ranged in age from 45 to 93 years, with an average age of 60.6 years in the HIV-positive group and 68.2 years in the HIV-negative group. Demographic data, Pittsburgh Sleep Quality Index score, and valid actigraphy (measured with an accelerometer for 14 consecutive days) were available for 172 participants (18% with HIV). A subgroup of 51 participants (22% with HIV) also had valid dim light melatonin onset (DLMO) data, a sensitive measure of the internal circadian clock. DLMO was measured for a minimum of 5 consecutive days with hourly saliva sampling between 5 p.m. and 11 p.m. while sitting in a dimly lit room.
In 36 participants (16% with HIV) with both valid actigraphy and DLMO data, circadian phase angle of entrainment was calculated by subtracting DLMO time from habitual sleep-onset time obtained from actigraphy.
After adjustment for age and sex, the study found a slightly later sleep onset (adjusted average delay of 10 minutes), earlier awakening (adjusted average advance of 10 minutes), and shorter sleep duration in PLWH compared with HIV-negative participants.
At the same time, melatonin production in PLWH started more than an hour later on average than in HIV-negative participants, “with half of the HIV+ group having an earlier habitual sleep onset than DLMO time” the authors wrote. In a subgroup of 36 participants with both valid actigraphy and DLMO data, the median circadian phase angle of entrainment was smaller in PLWH (–6 minutes vs. +1 hour 25 minutes in the HIV-negative group).
“Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants,” they added.
Asynchrony between bedtime and circadian time
“Ideally, with this delayed timing of circadian phase, they should have delayed their sleep phase (sleep timing) by an equal amount to be sleeping at their optimal biological time,” Dr. Scheuermaier explained. “Their sleep onset was delayed by 12 minutes (statistically significant but biologically not that much) while their circadian phase was delayed by more than an hour.”
Possible consequences of a smaller phase angle of entrainment include difficulty in initiating and maintaining sleep, the authors wrote. “The shorter, potentially mistimed sleep relative to the endogenous circadian cycle observed in this study provides objectively measured evidence supporting the abundant previous subjective reports of poor sleep quality and insomnia in PLWH.”
They noted that a strength of their study is that participants were recruited from rural South Africa, where HIV prevalence is not confined to the so-called “high-risk” groups of gay men, other men who have sex with men, people who inject drugs, and sex workers.
“Behavioral factors associated with belonging to one or more of these groups would be strong potential confounders for studies of sleep and circadian phase,” they explained. “By contrast, in rural southern Africa, the epidemic has been less demographically discriminating ... There are no notable differences in lifestyle between the HIV– and HIV+ individuals in this study. The members of this aging population are mostly beyond retirement age, living quiet, rural lives supported by government remittances and subsistence farming.”
Direct evidence warrants further study
The study is “unique” in that it provides “the first direct evidence for potential circadian disturbances in PWLH,” agreed Peng Li, PhD, who was not involved in the study.
“The assessment of dim light melatonin onset in PLWH is a strength of the study; together with actigraphy-based sleep onset assessment, it provides a measure for the phase angle of entrainment,” said Dr. Li, who is research director of the medical biodynamics program, division of sleep and circadian disorders, Brigham and Women’s Hospital, Boston.
But actigraphy has limitations that affect the interpretation of the results, he told this news organization.
“Without the help of sleep diaries, low specificity in assessing sleep using actigraphy has been consistently reported,” he said. “The low specificity means a significant overestimation of sleep. This lowers the value of the reported sleep readouts and limits the validity of sleep onset estimation, especially considering that differences in sleep measures between the two groups are relatively small, compromising the clinical meaning.”
Additionally, he explained that it’s not clear whether sleep onset in the study participants was spontaneous or was “forced” to accommodate routines. “This is a limitation in field study as compared with in-lab studies,” he said.
Dr. Li also pointed to the small sample size and younger age of PLWH, suggesting the study might have benefited from a matched design. Finally, he said the study did not examine gender differences.
“In the general population, it is known that females usually have advanced circadian phase compared to males. ... More rigorous design and analyses based on sex/gender especially in this often-marginalized population are warranted to better inform HIV-specific or general clinical guidelines.”
The study was supported by the Academy of Medical Sciences. The authors did not mention any competing interests. Dr. Li reported grant support from the BrightFocus Foundation. The study is not directly related to this paper. He also receives grant support from the NIH through a Departmental Award, Harvard University Center for AIDS Research and a Pilot Project, HIV and Aging Research Consortium. The projects are on circadian disturbances and cognitive performance in PLWH.
A version of this article first appeared on Medscape.com.
, according to findings that suggest both a possible mechanism for increased comorbidities in PLWH and potential solutions.
“It is very well known that sleep problems are common in people living with HIV, and many different reasons for this have been proposed,” coauthor Malcolm von Schantz, PhD, professor of chronobiology at Northumbria University in Newcastle upon Tyne, England, said in an interview. “But the novelty of our findings is the observation of delayed circadian rhythms.”
The mistimed circadian phase in PLWH is linked to later sleep onset and earlier waking and has “important potential implications” for the health and well-being of PLWH, wrote senior author Karine Scheuermaier, MD, from the University of the Witwatersrand, in Johannesburg, South Africa, and coauthors.
Until now, research on sleep in HIV has focused primarily on its homeostatic components, such as sleep duration and staging, rather than on circadian-related aspects, they noted.
“If the lifestyle‐independent circadian misalignment observed in the current study is confirmed to be a constant feature of chronic HIV infection, then it may be a mediator both of poorer sleep health and of poorer physical health in PLWH, which could potentially be alleviated through light therapy or chronobiotic medication or supplements,” they suggested.
HIV endemic in study population
The study analyzed a random sample of 187 participants (36 with HIV and 151 without) in the HAALSI (Health and Ageing in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) study, which is part of the Agincourt Health and Socio-demographic Surveillance System.
The study population ranged in age from 45 to 93 years, with an average age of 60.6 years in the HIV-positive group and 68.2 years in the HIV-negative group. Demographic data, Pittsburgh Sleep Quality Index score, and valid actigraphy (measured with an accelerometer for 14 consecutive days) were available for 172 participants (18% with HIV). A subgroup of 51 participants (22% with HIV) also had valid dim light melatonin onset (DLMO) data, a sensitive measure of the internal circadian clock. DLMO was measured for a minimum of 5 consecutive days with hourly saliva sampling between 5 p.m. and 11 p.m. while sitting in a dimly lit room.
In 36 participants (16% with HIV) with both valid actigraphy and DLMO data, circadian phase angle of entrainment was calculated by subtracting DLMO time from habitual sleep-onset time obtained from actigraphy.
After adjustment for age and sex, the study found a slightly later sleep onset (adjusted average delay of 10 minutes), earlier awakening (adjusted average advance of 10 minutes), and shorter sleep duration in PLWH compared with HIV-negative participants.
At the same time, melatonin production in PLWH started more than an hour later on average than in HIV-negative participants, “with half of the HIV+ group having an earlier habitual sleep onset than DLMO time” the authors wrote. In a subgroup of 36 participants with both valid actigraphy and DLMO data, the median circadian phase angle of entrainment was smaller in PLWH (–6 minutes vs. +1 hour 25 minutes in the HIV-negative group).
“Collectively, our data suggest that the sleep phase occurred earlier than what would be biologically optimal among the HIV+ participants,” they added.
Asynchrony between bedtime and circadian time
“Ideally, with this delayed timing of circadian phase, they should have delayed their sleep phase (sleep timing) by an equal amount to be sleeping at their optimal biological time,” Dr. Scheuermaier explained. “Their sleep onset was delayed by 12 minutes (statistically significant but biologically not that much) while their circadian phase was delayed by more than an hour.”
Possible consequences of a smaller phase angle of entrainment include difficulty in initiating and maintaining sleep, the authors wrote. “The shorter, potentially mistimed sleep relative to the endogenous circadian cycle observed in this study provides objectively measured evidence supporting the abundant previous subjective reports of poor sleep quality and insomnia in PLWH.”
They noted that a strength of their study is that participants were recruited from rural South Africa, where HIV prevalence is not confined to the so-called “high-risk” groups of gay men, other men who have sex with men, people who inject drugs, and sex workers.
“Behavioral factors associated with belonging to one or more of these groups would be strong potential confounders for studies of sleep and circadian phase,” they explained. “By contrast, in rural southern Africa, the epidemic has been less demographically discriminating ... There are no notable differences in lifestyle between the HIV– and HIV+ individuals in this study. The members of this aging population are mostly beyond retirement age, living quiet, rural lives supported by government remittances and subsistence farming.”
Direct evidence warrants further study
The study is “unique” in that it provides “the first direct evidence for potential circadian disturbances in PWLH,” agreed Peng Li, PhD, who was not involved in the study.
“The assessment of dim light melatonin onset in PLWH is a strength of the study; together with actigraphy-based sleep onset assessment, it provides a measure for the phase angle of entrainment,” said Dr. Li, who is research director of the medical biodynamics program, division of sleep and circadian disorders, Brigham and Women’s Hospital, Boston.
But actigraphy has limitations that affect the interpretation of the results, he told this news organization.
“Without the help of sleep diaries, low specificity in assessing sleep using actigraphy has been consistently reported,” he said. “The low specificity means a significant overestimation of sleep. This lowers the value of the reported sleep readouts and limits the validity of sleep onset estimation, especially considering that differences in sleep measures between the two groups are relatively small, compromising the clinical meaning.”
Additionally, he explained that it’s not clear whether sleep onset in the study participants was spontaneous or was “forced” to accommodate routines. “This is a limitation in field study as compared with in-lab studies,” he said.
Dr. Li also pointed to the small sample size and younger age of PLWH, suggesting the study might have benefited from a matched design. Finally, he said the study did not examine gender differences.
“In the general population, it is known that females usually have advanced circadian phase compared to males. ... More rigorous design and analyses based on sex/gender especially in this often-marginalized population are warranted to better inform HIV-specific or general clinical guidelines.”
The study was supported by the Academy of Medical Sciences. The authors did not mention any competing interests. Dr. Li reported grant support from the BrightFocus Foundation. The study is not directly related to this paper. He also receives grant support from the NIH through a Departmental Award, Harvard University Center for AIDS Research and a Pilot Project, HIV and Aging Research Consortium. The projects are on circadian disturbances and cognitive performance in PLWH.
A version of this article first appeared on Medscape.com.
FROM JOURNAL OF PINEAL RESEARCH
New statement guides the diagnosis of pediatric anxiety
The Canadian Paediatric Society (CPS) has issued a position statement on the diagnosis of anxiety disorders in children and youth. The organization aims to “offer evidence-informed guidance to support pediatric health care providers making decisions around the care of children and adolescents with these conditions.”
“It’s been a long time coming,” lead author Benjamin Klein, MD, assistant clinical professor of pediatrics at McMaster University, Hamilton, Ont., told this news organization. The target audience for the documents includes community pediatricians, subspecialists, family doctors, and nurse practitioners. “There was a great demand from that audience for a position statement, for guidance, obviously in the backdrop of rising child and adolescent mental health incidence over the years and of course COVID,” said Dr. Klein.
The statement was published on the CPS website.
‘A comprehensive approach’
Although many other guidelines on this topic are available, it was important to have a Canadian document, said Dr. Klein. “Obviously, there’s going to be a great deal of overlap with European or American guidelines, but it’s just kind of assumed that people want specifically Canadian content. ... Physicians want to know that they’re practicing within a standard of care in Canada.” Dr. Klein is medical director of the Lansdowne Children’s Centre, Brantford, Ont., which provides help for children with communication, developmental, and physical special needs across Ontario.
Anxiety disorders are the most common mental disorders among children and adolescents in Canada, according to the position statement. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) groups these disorders into separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, agoraphobia, and generalized anxiety disorder.
Distinguishing normal, age-appropriate anxiety from anxiety disorder, while also recognizing other comorbidities, is complicated, said Dr. Klein. “Anxiety is one possible diagnosis or feature, and children with mental health and developmental problems often present with a number of problems. Anxiety may be one of them, but if it’s one of them, it may not be the main driver. So, a comprehensive approach is needed ... combining the medical model with biopsychosocial thinking to give a better picture of anxiety in the context of anything else that may be contributing to a presentation.”
The statement outlines recommendations for anxiety assessment, starting with a screening questionnaire such as the Screen for Child Anxiety Related Disorders (SCARED), which is completed by parents and children, to assess symptom severity. Standardized measures for medical, mental health, and developmental histories are available on the CPS website.
The document next recommends an interview about presenting concerns (such as sleep problems or school difficulties), inciting events, and parent-child interactions. The process includes confidential, nonjudgmental interviews with adolescents using a history-taking tool such as HEEADSSS (Home, Education/Employment, Eating, Activities, Drugs, Sexuality, Suicide/Mental Health, and Safety).
“The diagnosis and treatment of anxiety disorders kind of sounds simple if you just read about it as an isolated thing, but the reality is ... there’s no MRI. It’s detective work,” said Dr. Klein. Clinicians must distinguish between normal anxiety, situational anxiety, and specific anxiety disorder, he added. He usually allows 90 minutes for an anxiety assessment, partly to gain the patient’s trust. “These are sensitive issues. It’s common that people don’t trust a diagnosis if you haven’t spent enough time with them. That relational care piece just needs to be there, or people aren’t going to buy in.”
The CPS position statement was reviewed and endorsed by the Canadian Academy of Child and Adolescent Psychiatry.
Methodology unclear
Joanna Henderson, MD, professor of psychiatry at the University of Toronto and director of the Margaret and Wallace McCain Centre for Child, Youth, and Family Mental Health at the Centre for Addiction and Mental Health, Toronto, said that the guidelines have been released at an important time. “Conversations about mental health have become more common, and many children, youth, and families are reaching out for support. It is essential that health care professionals be equipped with accessible information about practices to provide appropriate care. These guidelines support that vision.”
It would be helpful to know more about the methods used to arrive at the recommendations, however, said Dr. Henderson. “It is critical that health care providers be guided by evidence-based guidelines that adhere to criteria for establishing high-quality guidelines. Because the authors did not provide information about their methods, I am not able to provide a comment about the quality of their guidelines. There are established approaches for evaluating quality, and I would encourage the authors to publish as a supplement to this article their methods, including in reference to the Appraisal of Guidelines for Research and Evaluation (AGREE II) checklist.”
In the absence of readily available information about methods, she said, “clinicians are encouraged to use guidelines from sources that provide information about the guideline development process and include quality appraisal,” such as the UK National Institute for Health and Care Excellence, which is “generally recognized as a reputable source for high-quality practice guidelines.”
Responding to this concern, Dr. Klein said, “There is no specific evidence base for diagnosis. That robust science doesn’t exist. No one has done randomized controlled trials of different methods of diagnosing kids with anxiety. We looked at other position statements, we looked at textbooks, and obviously we drew from our own clinical experience, so it comes from clinical judgment and expert opinion.”
Dr. Henderson also noted that in the future “it will be important to contextualize the recommendations by highlighting the importance of cultural competence in conducting assessments and providing treatment.” Moreover, current evidence can be expanded through the incorporation of diverse cultural and racial perspectives, experiences, and data, she added.
Health service providers should reflect on their own potential biases, which can influence clinician-patient interactions, Dr. Henderson continued. It also is important to consider biases in the evidence, which influence practice. Clinicians should also consider how their recommendations fit with patients’ “cultural and race-based experiences, beliefs, and practices.”
No source of funding for the position statement was reported. Dr. Klein and Dr. Henderson had disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The Canadian Paediatric Society (CPS) has issued a position statement on the diagnosis of anxiety disorders in children and youth. The organization aims to “offer evidence-informed guidance to support pediatric health care providers making decisions around the care of children and adolescents with these conditions.”
“It’s been a long time coming,” lead author Benjamin Klein, MD, assistant clinical professor of pediatrics at McMaster University, Hamilton, Ont., told this news organization. The target audience for the documents includes community pediatricians, subspecialists, family doctors, and nurse practitioners. “There was a great demand from that audience for a position statement, for guidance, obviously in the backdrop of rising child and adolescent mental health incidence over the years and of course COVID,” said Dr. Klein.
The statement was published on the CPS website.
‘A comprehensive approach’
Although many other guidelines on this topic are available, it was important to have a Canadian document, said Dr. Klein. “Obviously, there’s going to be a great deal of overlap with European or American guidelines, but it’s just kind of assumed that people want specifically Canadian content. ... Physicians want to know that they’re practicing within a standard of care in Canada.” Dr. Klein is medical director of the Lansdowne Children’s Centre, Brantford, Ont., which provides help for children with communication, developmental, and physical special needs across Ontario.
Anxiety disorders are the most common mental disorders among children and adolescents in Canada, according to the position statement. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) groups these disorders into separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, agoraphobia, and generalized anxiety disorder.
Distinguishing normal, age-appropriate anxiety from anxiety disorder, while also recognizing other comorbidities, is complicated, said Dr. Klein. “Anxiety is one possible diagnosis or feature, and children with mental health and developmental problems often present with a number of problems. Anxiety may be one of them, but if it’s one of them, it may not be the main driver. So, a comprehensive approach is needed ... combining the medical model with biopsychosocial thinking to give a better picture of anxiety in the context of anything else that may be contributing to a presentation.”
The statement outlines recommendations for anxiety assessment, starting with a screening questionnaire such as the Screen for Child Anxiety Related Disorders (SCARED), which is completed by parents and children, to assess symptom severity. Standardized measures for medical, mental health, and developmental histories are available on the CPS website.
The document next recommends an interview about presenting concerns (such as sleep problems or school difficulties), inciting events, and parent-child interactions. The process includes confidential, nonjudgmental interviews with adolescents using a history-taking tool such as HEEADSSS (Home, Education/Employment, Eating, Activities, Drugs, Sexuality, Suicide/Mental Health, and Safety).
“The diagnosis and treatment of anxiety disorders kind of sounds simple if you just read about it as an isolated thing, but the reality is ... there’s no MRI. It’s detective work,” said Dr. Klein. Clinicians must distinguish between normal anxiety, situational anxiety, and specific anxiety disorder, he added. He usually allows 90 minutes for an anxiety assessment, partly to gain the patient’s trust. “These are sensitive issues. It’s common that people don’t trust a diagnosis if you haven’t spent enough time with them. That relational care piece just needs to be there, or people aren’t going to buy in.”
The CPS position statement was reviewed and endorsed by the Canadian Academy of Child and Adolescent Psychiatry.
Methodology unclear
Joanna Henderson, MD, professor of psychiatry at the University of Toronto and director of the Margaret and Wallace McCain Centre for Child, Youth, and Family Mental Health at the Centre for Addiction and Mental Health, Toronto, said that the guidelines have been released at an important time. “Conversations about mental health have become more common, and many children, youth, and families are reaching out for support. It is essential that health care professionals be equipped with accessible information about practices to provide appropriate care. These guidelines support that vision.”
It would be helpful to know more about the methods used to arrive at the recommendations, however, said Dr. Henderson. “It is critical that health care providers be guided by evidence-based guidelines that adhere to criteria for establishing high-quality guidelines. Because the authors did not provide information about their methods, I am not able to provide a comment about the quality of their guidelines. There are established approaches for evaluating quality, and I would encourage the authors to publish as a supplement to this article their methods, including in reference to the Appraisal of Guidelines for Research and Evaluation (AGREE II) checklist.”
In the absence of readily available information about methods, she said, “clinicians are encouraged to use guidelines from sources that provide information about the guideline development process and include quality appraisal,” such as the UK National Institute for Health and Care Excellence, which is “generally recognized as a reputable source for high-quality practice guidelines.”
Responding to this concern, Dr. Klein said, “There is no specific evidence base for diagnosis. That robust science doesn’t exist. No one has done randomized controlled trials of different methods of diagnosing kids with anxiety. We looked at other position statements, we looked at textbooks, and obviously we drew from our own clinical experience, so it comes from clinical judgment and expert opinion.”
Dr. Henderson also noted that in the future “it will be important to contextualize the recommendations by highlighting the importance of cultural competence in conducting assessments and providing treatment.” Moreover, current evidence can be expanded through the incorporation of diverse cultural and racial perspectives, experiences, and data, she added.
Health service providers should reflect on their own potential biases, which can influence clinician-patient interactions, Dr. Henderson continued. It also is important to consider biases in the evidence, which influence practice. Clinicians should also consider how their recommendations fit with patients’ “cultural and race-based experiences, beliefs, and practices.”
No source of funding for the position statement was reported. Dr. Klein and Dr. Henderson had disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The Canadian Paediatric Society (CPS) has issued a position statement on the diagnosis of anxiety disorders in children and youth. The organization aims to “offer evidence-informed guidance to support pediatric health care providers making decisions around the care of children and adolescents with these conditions.”
“It’s been a long time coming,” lead author Benjamin Klein, MD, assistant clinical professor of pediatrics at McMaster University, Hamilton, Ont., told this news organization. The target audience for the documents includes community pediatricians, subspecialists, family doctors, and nurse practitioners. “There was a great demand from that audience for a position statement, for guidance, obviously in the backdrop of rising child and adolescent mental health incidence over the years and of course COVID,” said Dr. Klein.
The statement was published on the CPS website.
‘A comprehensive approach’
Although many other guidelines on this topic are available, it was important to have a Canadian document, said Dr. Klein. “Obviously, there’s going to be a great deal of overlap with European or American guidelines, but it’s just kind of assumed that people want specifically Canadian content. ... Physicians want to know that they’re practicing within a standard of care in Canada.” Dr. Klein is medical director of the Lansdowne Children’s Centre, Brantford, Ont., which provides help for children with communication, developmental, and physical special needs across Ontario.
Anxiety disorders are the most common mental disorders among children and adolescents in Canada, according to the position statement. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) groups these disorders into separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, agoraphobia, and generalized anxiety disorder.
Distinguishing normal, age-appropriate anxiety from anxiety disorder, while also recognizing other comorbidities, is complicated, said Dr. Klein. “Anxiety is one possible diagnosis or feature, and children with mental health and developmental problems often present with a number of problems. Anxiety may be one of them, but if it’s one of them, it may not be the main driver. So, a comprehensive approach is needed ... combining the medical model with biopsychosocial thinking to give a better picture of anxiety in the context of anything else that may be contributing to a presentation.”
The statement outlines recommendations for anxiety assessment, starting with a screening questionnaire such as the Screen for Child Anxiety Related Disorders (SCARED), which is completed by parents and children, to assess symptom severity. Standardized measures for medical, mental health, and developmental histories are available on the CPS website.
The document next recommends an interview about presenting concerns (such as sleep problems or school difficulties), inciting events, and parent-child interactions. The process includes confidential, nonjudgmental interviews with adolescents using a history-taking tool such as HEEADSSS (Home, Education/Employment, Eating, Activities, Drugs, Sexuality, Suicide/Mental Health, and Safety).
“The diagnosis and treatment of anxiety disorders kind of sounds simple if you just read about it as an isolated thing, but the reality is ... there’s no MRI. It’s detective work,” said Dr. Klein. Clinicians must distinguish between normal anxiety, situational anxiety, and specific anxiety disorder, he added. He usually allows 90 minutes for an anxiety assessment, partly to gain the patient’s trust. “These are sensitive issues. It’s common that people don’t trust a diagnosis if you haven’t spent enough time with them. That relational care piece just needs to be there, or people aren’t going to buy in.”
The CPS position statement was reviewed and endorsed by the Canadian Academy of Child and Adolescent Psychiatry.
Methodology unclear
Joanna Henderson, MD, professor of psychiatry at the University of Toronto and director of the Margaret and Wallace McCain Centre for Child, Youth, and Family Mental Health at the Centre for Addiction and Mental Health, Toronto, said that the guidelines have been released at an important time. “Conversations about mental health have become more common, and many children, youth, and families are reaching out for support. It is essential that health care professionals be equipped with accessible information about practices to provide appropriate care. These guidelines support that vision.”
It would be helpful to know more about the methods used to arrive at the recommendations, however, said Dr. Henderson. “It is critical that health care providers be guided by evidence-based guidelines that adhere to criteria for establishing high-quality guidelines. Because the authors did not provide information about their methods, I am not able to provide a comment about the quality of their guidelines. There are established approaches for evaluating quality, and I would encourage the authors to publish as a supplement to this article their methods, including in reference to the Appraisal of Guidelines for Research and Evaluation (AGREE II) checklist.”
In the absence of readily available information about methods, she said, “clinicians are encouraged to use guidelines from sources that provide information about the guideline development process and include quality appraisal,” such as the UK National Institute for Health and Care Excellence, which is “generally recognized as a reputable source for high-quality practice guidelines.”
Responding to this concern, Dr. Klein said, “There is no specific evidence base for diagnosis. That robust science doesn’t exist. No one has done randomized controlled trials of different methods of diagnosing kids with anxiety. We looked at other position statements, we looked at textbooks, and obviously we drew from our own clinical experience, so it comes from clinical judgment and expert opinion.”
Dr. Henderson also noted that in the future “it will be important to contextualize the recommendations by highlighting the importance of cultural competence in conducting assessments and providing treatment.” Moreover, current evidence can be expanded through the incorporation of diverse cultural and racial perspectives, experiences, and data, she added.
Health service providers should reflect on their own potential biases, which can influence clinician-patient interactions, Dr. Henderson continued. It also is important to consider biases in the evidence, which influence practice. Clinicians should also consider how their recommendations fit with patients’ “cultural and race-based experiences, beliefs, and practices.”
No source of funding for the position statement was reported. Dr. Klein and Dr. Henderson had disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Rapid action or sustained effect? Methotrexate vs. ciclosporin for pediatric AD
MONTREAL – in the TREAT study, investigators reported at the annual meeting of the International Society of Atopic Dermatitis.
The findings are important, since many regulatory bodies require patients to have tried such first-line conventional systemic therapies before moving on to novel therapeutics, explained Carsten Flohr, MD, PhD, research and development lead at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust London.
“We don’t really have much pediatric trial data; very often the pediatric data that we have is buried in adult trials and when it comes to an adequately powered randomized controlled trial with conventional systemic medication in pediatric patients, we don’t have one – so we’re lacking that gold standard,” said Dr. Flohr, chair in dermatology and population health sciences at King’s College London.
In the TREAT trial, 103 patients with AD (mean age, 10 years) who had not responded to topical treatment, were randomly assigned to oral ciclosporin (4 mg/kg daily) or methotrexate (0.4 mg/kg weekly) for 36 weeks and then followed for another 24 weeks off therapy for the co-primary outcomes of change in objective Scoring Atopic Dermatitis (o-SCORAD) at 12 weeks, as well as time to first significant flare after treatment cessation, defined as returning to baseline o-SCORAD, or restarting a systemic treatment.
Secondary outcomes included disease severity and quality of life (QOL) measures, as well as safety. At baseline, the mean o-SCORAD was 46.81, with mean Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM) scores of 28.05 and 20.62 respectively. The mean Children’s Dermatology Life Quality Index (CDLQI) score was 14.96.
Looking at change in eczema severity measured by o-SCORAD at 12 weeks, ciclosporin was superior to methotrexate, with a mean difference in o-SCORAD change of -5.69 (P =.01). For the co-primary endpoint of time to first significant flare during the 24 weeks after treatment cessation, “there was a trend toward more flare activity in the ciclosporin group, although with a hazard ratio of 1.55, this was statistically not significant,” Dr. Flohr said.
On a graph showing mean EASI scores from baseline through the 60-week study period, Dr. Flohr explained how the score first dropped more precipitously in patients treated with ciclosporin compared with those treated with methotrexate, reaching a statistically significant difference between the groups by 12 weeks (–3.13, P = .0145).
However, after that time, while the EASI score among those on methotrexate continued to drop, the ciclosporin score evened out, so that by 20 weeks, methotrexate EASI scores were better, and remained so until the end of treatment and further, out to 60 weeks (mean difference -6.36, P < .001). “The most interesting bit of this graph is [that] the curve is pointing downwards for methotrexate up to the 9-month point, suggesting these people had not reached their full therapeutic potential yet, whereas if you’re on ciclosporin you plateau and there’s not much additional improvement, if at all, and then people [on ciclosporin] start going up in their disease activity off therapy,” he said.
The same pattern was seen with all the other outcome measures, including o-SCORAD and POEM.
Quality of life significantly improved by about 8 points in both treatment groups, with no significant differences between groups, and this improvement was sustained through the 24 weeks following cessation of therapy. However, during this treatment-free phase, patients on methotrexate had fewer parent-reported flares compared with those on ciclosporin (mean 6.19 vs 5.40 flares, P =.0251), although there was no difference between groups in time to first flare.
Describing the treatment safety as “overall reassuring,” Dr. Flohr said there were slightly more nonserious adverse events in the methotrexate arm (407 vs. 369), with nausea occurring more often in this group (43.1% vs. 17.6%).
“I think we were seeing this clinically, but to see it in a clinical trial gives us more confidence in discussing with parents,” said session moderator Melinda Gooderham, MD, assistant professor at Queens University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology in Peterborough.
What she also took away from the study was safety of these treatments. “The discontinuation rate was not different with either drug, so it’s not like ciclosporin works fast but all these people have problems and discontinue,” Dr. Gooderham told this news organization. “That’s also reassuring.”
Asked which treatment she prefers, Dr. Gooderham, a consultant physician at Peterborough Regional Health Centre, picked methotrexate “because of the lasting effect. But there are times when you may need more rapid control ... where I might choose ciclosporin first, but for me it’s maybe 90% methotrexate first, 10% ciclosporin.”
Dr. Flohr and Dr. Gooderham report no relevant financial relationships. The study was funded by the National Institute for Health and Care Research.
A version of this article first appeared on Medscape.com.
MONTREAL – in the TREAT study, investigators reported at the annual meeting of the International Society of Atopic Dermatitis.
The findings are important, since many regulatory bodies require patients to have tried such first-line conventional systemic therapies before moving on to novel therapeutics, explained Carsten Flohr, MD, PhD, research and development lead at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust London.
“We don’t really have much pediatric trial data; very often the pediatric data that we have is buried in adult trials and when it comes to an adequately powered randomized controlled trial with conventional systemic medication in pediatric patients, we don’t have one – so we’re lacking that gold standard,” said Dr. Flohr, chair in dermatology and population health sciences at King’s College London.
In the TREAT trial, 103 patients with AD (mean age, 10 years) who had not responded to topical treatment, were randomly assigned to oral ciclosporin (4 mg/kg daily) or methotrexate (0.4 mg/kg weekly) for 36 weeks and then followed for another 24 weeks off therapy for the co-primary outcomes of change in objective Scoring Atopic Dermatitis (o-SCORAD) at 12 weeks, as well as time to first significant flare after treatment cessation, defined as returning to baseline o-SCORAD, or restarting a systemic treatment.
Secondary outcomes included disease severity and quality of life (QOL) measures, as well as safety. At baseline, the mean o-SCORAD was 46.81, with mean Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM) scores of 28.05 and 20.62 respectively. The mean Children’s Dermatology Life Quality Index (CDLQI) score was 14.96.
Looking at change in eczema severity measured by o-SCORAD at 12 weeks, ciclosporin was superior to methotrexate, with a mean difference in o-SCORAD change of -5.69 (P =.01). For the co-primary endpoint of time to first significant flare during the 24 weeks after treatment cessation, “there was a trend toward more flare activity in the ciclosporin group, although with a hazard ratio of 1.55, this was statistically not significant,” Dr. Flohr said.
On a graph showing mean EASI scores from baseline through the 60-week study period, Dr. Flohr explained how the score first dropped more precipitously in patients treated with ciclosporin compared with those treated with methotrexate, reaching a statistically significant difference between the groups by 12 weeks (–3.13, P = .0145).
However, after that time, while the EASI score among those on methotrexate continued to drop, the ciclosporin score evened out, so that by 20 weeks, methotrexate EASI scores were better, and remained so until the end of treatment and further, out to 60 weeks (mean difference -6.36, P < .001). “The most interesting bit of this graph is [that] the curve is pointing downwards for methotrexate up to the 9-month point, suggesting these people had not reached their full therapeutic potential yet, whereas if you’re on ciclosporin you plateau and there’s not much additional improvement, if at all, and then people [on ciclosporin] start going up in their disease activity off therapy,” he said.
The same pattern was seen with all the other outcome measures, including o-SCORAD and POEM.
Quality of life significantly improved by about 8 points in both treatment groups, with no significant differences between groups, and this improvement was sustained through the 24 weeks following cessation of therapy. However, during this treatment-free phase, patients on methotrexate had fewer parent-reported flares compared with those on ciclosporin (mean 6.19 vs 5.40 flares, P =.0251), although there was no difference between groups in time to first flare.
Describing the treatment safety as “overall reassuring,” Dr. Flohr said there were slightly more nonserious adverse events in the methotrexate arm (407 vs. 369), with nausea occurring more often in this group (43.1% vs. 17.6%).
“I think we were seeing this clinically, but to see it in a clinical trial gives us more confidence in discussing with parents,” said session moderator Melinda Gooderham, MD, assistant professor at Queens University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology in Peterborough.
What she also took away from the study was safety of these treatments. “The discontinuation rate was not different with either drug, so it’s not like ciclosporin works fast but all these people have problems and discontinue,” Dr. Gooderham told this news organization. “That’s also reassuring.”
Asked which treatment she prefers, Dr. Gooderham, a consultant physician at Peterborough Regional Health Centre, picked methotrexate “because of the lasting effect. But there are times when you may need more rapid control ... where I might choose ciclosporin first, but for me it’s maybe 90% methotrexate first, 10% ciclosporin.”
Dr. Flohr and Dr. Gooderham report no relevant financial relationships. The study was funded by the National Institute for Health and Care Research.
A version of this article first appeared on Medscape.com.
MONTREAL – in the TREAT study, investigators reported at the annual meeting of the International Society of Atopic Dermatitis.
The findings are important, since many regulatory bodies require patients to have tried such first-line conventional systemic therapies before moving on to novel therapeutics, explained Carsten Flohr, MD, PhD, research and development lead at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust London.
“We don’t really have much pediatric trial data; very often the pediatric data that we have is buried in adult trials and when it comes to an adequately powered randomized controlled trial with conventional systemic medication in pediatric patients, we don’t have one – so we’re lacking that gold standard,” said Dr. Flohr, chair in dermatology and population health sciences at King’s College London.
In the TREAT trial, 103 patients with AD (mean age, 10 years) who had not responded to topical treatment, were randomly assigned to oral ciclosporin (4 mg/kg daily) or methotrexate (0.4 mg/kg weekly) for 36 weeks and then followed for another 24 weeks off therapy for the co-primary outcomes of change in objective Scoring Atopic Dermatitis (o-SCORAD) at 12 weeks, as well as time to first significant flare after treatment cessation, defined as returning to baseline o-SCORAD, or restarting a systemic treatment.
Secondary outcomes included disease severity and quality of life (QOL) measures, as well as safety. At baseline, the mean o-SCORAD was 46.81, with mean Eczema Area and Severity Index (EASI) and Patient Oriented Eczema Measure (POEM) scores of 28.05 and 20.62 respectively. The mean Children’s Dermatology Life Quality Index (CDLQI) score was 14.96.
Looking at change in eczema severity measured by o-SCORAD at 12 weeks, ciclosporin was superior to methotrexate, with a mean difference in o-SCORAD change of -5.69 (P =.01). For the co-primary endpoint of time to first significant flare during the 24 weeks after treatment cessation, “there was a trend toward more flare activity in the ciclosporin group, although with a hazard ratio of 1.55, this was statistically not significant,” Dr. Flohr said.
On a graph showing mean EASI scores from baseline through the 60-week study period, Dr. Flohr explained how the score first dropped more precipitously in patients treated with ciclosporin compared with those treated with methotrexate, reaching a statistically significant difference between the groups by 12 weeks (–3.13, P = .0145).
However, after that time, while the EASI score among those on methotrexate continued to drop, the ciclosporin score evened out, so that by 20 weeks, methotrexate EASI scores were better, and remained so until the end of treatment and further, out to 60 weeks (mean difference -6.36, P < .001). “The most interesting bit of this graph is [that] the curve is pointing downwards for methotrexate up to the 9-month point, suggesting these people had not reached their full therapeutic potential yet, whereas if you’re on ciclosporin you plateau and there’s not much additional improvement, if at all, and then people [on ciclosporin] start going up in their disease activity off therapy,” he said.
The same pattern was seen with all the other outcome measures, including o-SCORAD and POEM.
Quality of life significantly improved by about 8 points in both treatment groups, with no significant differences between groups, and this improvement was sustained through the 24 weeks following cessation of therapy. However, during this treatment-free phase, patients on methotrexate had fewer parent-reported flares compared with those on ciclosporin (mean 6.19 vs 5.40 flares, P =.0251), although there was no difference between groups in time to first flare.
Describing the treatment safety as “overall reassuring,” Dr. Flohr said there were slightly more nonserious adverse events in the methotrexate arm (407 vs. 369), with nausea occurring more often in this group (43.1% vs. 17.6%).
“I think we were seeing this clinically, but to see it in a clinical trial gives us more confidence in discussing with parents,” said session moderator Melinda Gooderham, MD, assistant professor at Queens University, Kingston, Ont., and medical director at the SKiN Centre for Dermatology in Peterborough.
What she also took away from the study was safety of these treatments. “The discontinuation rate was not different with either drug, so it’s not like ciclosporin works fast but all these people have problems and discontinue,” Dr. Gooderham told this news organization. “That’s also reassuring.”
Asked which treatment she prefers, Dr. Gooderham, a consultant physician at Peterborough Regional Health Centre, picked methotrexate “because of the lasting effect. But there are times when you may need more rapid control ... where I might choose ciclosporin first, but for me it’s maybe 90% methotrexate first, 10% ciclosporin.”
Dr. Flohr and Dr. Gooderham report no relevant financial relationships. The study was funded by the National Institute for Health and Care Research.
A version of this article first appeared on Medscape.com.
AT ISAD 2022
Online support tool improves AD self-management
MONTREAL – for up to 1 year, according to two randomized controlled trials presented at the annual meeting of the International Society of Atopic Dermatitis.
The intervention, directed either at parents of children with AD or young adults with AD, “is very low cost, evidence based, easily accessible, and free from possible commercial bias,” said investigator Kim Thomas, MD, professor of applied dermatology research and codirector of the Centre of Evidence Based Dermatology, faculty of medicine & health sciences, University of Nottingham (England).
The main focus of the intervention, along with general education, is “getting control” of the condition with flare-control creams and “keeping control” with regular emollient use.
Efficacy of the intervention, available free online, was compared with “usual eczema care” in 340 parents of children with AD up to age 12 and 337 young patients with AD aged 13-25. Participants were randomized to the intervention plus usual care or usual care alone. The primary outcome was the Patient-Oriented Eczema Measure(POEM) at 24 weeks, with a further measurement at 52 weeks.
In the parent group, about half were women and 83% were White, and the median age of their children was 4 years. About 50% of parents had a university degree, making them “possibly better educated than we might want our target audience for this type of intervention,” Dr. Thomas commented. Most of the children had moderate AD.
In the young patient group, the mean age was 19 years, more than three-quarters were female, 83% were White, and most had moderate AD.
At 24 weeks, both intervention groups had improved POEM scores, compared with controls, with a mean difference of 1.5 points in the parent group (P = .002) and 1.7 points in the young patient group (P = .04). “A small difference, but statistically significant and sustained,” Dr. Thomas said, adding that this difference was sustained up to 52 weeks.
In terms of mechanism of action, a secondary outcome looked at the concept of enablement, “which again, seemed to be improved in the intervention group, which suggests it’s something to do with being able to understand and cope with their disease better,” she said. The tool is targeted to “people who wouldn’t normally get to a dermatologist and certainly wouldn’t get access to group interventions.”
An additional aim of the intervention was “to provide a single, consistent message received from every point of contact that people might engage with ... [from] community doctors, pharmacists, dermatologists, and importantly, eczema charities all signposting [the intervention] and sharing a consistent message.”
While the intervention is free and available to patients anywhere, Dr. Thomas emphasized that it is tailored to the U.K. health care system. “If people would like to get in touch and help work with us to maybe adapt it slightly to make it more suitable for your own health care systems, that’s something we’d be very happy to look at with you.”
Asked for comment, Natalie Cunningham, MD, panel moderator, was lukewarm about the tool. “It can be a supplement, but you can never replace the one-on-one patient–health care provider interaction,” she told this news organization. “That could be provided by a nondermatologist and supplemented by an online component,” said Dr. Cunningham, from the Izaak Walton Killam Hospital for Children in Halifax, N.S.
“First-line treatment for eczema, no matter what kind of eczema, is topical steroids, and that is something that requires a lot of education – and something you want to do one on one in person because everyone comes to it with a different experience, baggage, or understanding,” she said. “We need to figure out what the barrier is so that you can do the right education.”
In addition, with systemic AD therapies currently approved for children, parents and young patients need to be able to advocate for specialist care to access these medications, she noted.
Dr. Thomas and Dr. Cunningham reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MONTREAL – for up to 1 year, according to two randomized controlled trials presented at the annual meeting of the International Society of Atopic Dermatitis.
The intervention, directed either at parents of children with AD or young adults with AD, “is very low cost, evidence based, easily accessible, and free from possible commercial bias,” said investigator Kim Thomas, MD, professor of applied dermatology research and codirector of the Centre of Evidence Based Dermatology, faculty of medicine & health sciences, University of Nottingham (England).
The main focus of the intervention, along with general education, is “getting control” of the condition with flare-control creams and “keeping control” with regular emollient use.
Efficacy of the intervention, available free online, was compared with “usual eczema care” in 340 parents of children with AD up to age 12 and 337 young patients with AD aged 13-25. Participants were randomized to the intervention plus usual care or usual care alone. The primary outcome was the Patient-Oriented Eczema Measure(POEM) at 24 weeks, with a further measurement at 52 weeks.
In the parent group, about half were women and 83% were White, and the median age of their children was 4 years. About 50% of parents had a university degree, making them “possibly better educated than we might want our target audience for this type of intervention,” Dr. Thomas commented. Most of the children had moderate AD.
In the young patient group, the mean age was 19 years, more than three-quarters were female, 83% were White, and most had moderate AD.
At 24 weeks, both intervention groups had improved POEM scores, compared with controls, with a mean difference of 1.5 points in the parent group (P = .002) and 1.7 points in the young patient group (P = .04). “A small difference, but statistically significant and sustained,” Dr. Thomas said, adding that this difference was sustained up to 52 weeks.
In terms of mechanism of action, a secondary outcome looked at the concept of enablement, “which again, seemed to be improved in the intervention group, which suggests it’s something to do with being able to understand and cope with their disease better,” she said. The tool is targeted to “people who wouldn’t normally get to a dermatologist and certainly wouldn’t get access to group interventions.”
An additional aim of the intervention was “to provide a single, consistent message received from every point of contact that people might engage with ... [from] community doctors, pharmacists, dermatologists, and importantly, eczema charities all signposting [the intervention] and sharing a consistent message.”
While the intervention is free and available to patients anywhere, Dr. Thomas emphasized that it is tailored to the U.K. health care system. “If people would like to get in touch and help work with us to maybe adapt it slightly to make it more suitable for your own health care systems, that’s something we’d be very happy to look at with you.”
Asked for comment, Natalie Cunningham, MD, panel moderator, was lukewarm about the tool. “It can be a supplement, but you can never replace the one-on-one patient–health care provider interaction,” she told this news organization. “That could be provided by a nondermatologist and supplemented by an online component,” said Dr. Cunningham, from the Izaak Walton Killam Hospital for Children in Halifax, N.S.
“First-line treatment for eczema, no matter what kind of eczema, is topical steroids, and that is something that requires a lot of education – and something you want to do one on one in person because everyone comes to it with a different experience, baggage, or understanding,” she said. “We need to figure out what the barrier is so that you can do the right education.”
In addition, with systemic AD therapies currently approved for children, parents and young patients need to be able to advocate for specialist care to access these medications, she noted.
Dr. Thomas and Dr. Cunningham reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MONTREAL – for up to 1 year, according to two randomized controlled trials presented at the annual meeting of the International Society of Atopic Dermatitis.
The intervention, directed either at parents of children with AD or young adults with AD, “is very low cost, evidence based, easily accessible, and free from possible commercial bias,” said investigator Kim Thomas, MD, professor of applied dermatology research and codirector of the Centre of Evidence Based Dermatology, faculty of medicine & health sciences, University of Nottingham (England).
The main focus of the intervention, along with general education, is “getting control” of the condition with flare-control creams and “keeping control” with regular emollient use.
Efficacy of the intervention, available free online, was compared with “usual eczema care” in 340 parents of children with AD up to age 12 and 337 young patients with AD aged 13-25. Participants were randomized to the intervention plus usual care or usual care alone. The primary outcome was the Patient-Oriented Eczema Measure(POEM) at 24 weeks, with a further measurement at 52 weeks.
In the parent group, about half were women and 83% were White, and the median age of their children was 4 years. About 50% of parents had a university degree, making them “possibly better educated than we might want our target audience for this type of intervention,” Dr. Thomas commented. Most of the children had moderate AD.
In the young patient group, the mean age was 19 years, more than three-quarters were female, 83% were White, and most had moderate AD.
At 24 weeks, both intervention groups had improved POEM scores, compared with controls, with a mean difference of 1.5 points in the parent group (P = .002) and 1.7 points in the young patient group (P = .04). “A small difference, but statistically significant and sustained,” Dr. Thomas said, adding that this difference was sustained up to 52 weeks.
In terms of mechanism of action, a secondary outcome looked at the concept of enablement, “which again, seemed to be improved in the intervention group, which suggests it’s something to do with being able to understand and cope with their disease better,” she said. The tool is targeted to “people who wouldn’t normally get to a dermatologist and certainly wouldn’t get access to group interventions.”
An additional aim of the intervention was “to provide a single, consistent message received from every point of contact that people might engage with ... [from] community doctors, pharmacists, dermatologists, and importantly, eczema charities all signposting [the intervention] and sharing a consistent message.”
While the intervention is free and available to patients anywhere, Dr. Thomas emphasized that it is tailored to the U.K. health care system. “If people would like to get in touch and help work with us to maybe adapt it slightly to make it more suitable for your own health care systems, that’s something we’d be very happy to look at with you.”
Asked for comment, Natalie Cunningham, MD, panel moderator, was lukewarm about the tool. “It can be a supplement, but you can never replace the one-on-one patient–health care provider interaction,” she told this news organization. “That could be provided by a nondermatologist and supplemented by an online component,” said Dr. Cunningham, from the Izaak Walton Killam Hospital for Children in Halifax, N.S.
“First-line treatment for eczema, no matter what kind of eczema, is topical steroids, and that is something that requires a lot of education – and something you want to do one on one in person because everyone comes to it with a different experience, baggage, or understanding,” she said. “We need to figure out what the barrier is so that you can do the right education.”
In addition, with systemic AD therapies currently approved for children, parents and young patients need to be able to advocate for specialist care to access these medications, she noted.
Dr. Thomas and Dr. Cunningham reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ISAD 2022